Compounds

ABSTRACT

The invention provides compounds of general formula (I) wherein Q, R, R 2 , R 4 , R 5 , R 6 , R 7  and R 8  are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a national phase application under 35 U.S.C.Section 371 filed from International Patent Application PCT/SE01/00404,filed 23 Feb. 2001, which claims priority to Swedish patent applicationSerial. No. 0000620-5, filed 25 Feb. 2000, Swedish patent applicationSerial. No. 0002234-3, filed 14 Jun. 2000, and Swedish patentapplication Serial. No. 0003979-2, filed 31 Oct. 2000. The contents ofthese applications are incorporated herein by reference in theirentirety.

The present invention relates to novel compounds, processes for theirpreparation, pharmaceutical compositions containing them and their usein therapy.

U.S. Pat. No. 5,789,402 describes certain indole deriatives which aresaid to be useful for the treatment of diseases which are caused oraffected by disorders of the serotonin-affected neurological systems,particularly those relating to the serotonin 1_(A) receptor and thoserelating to the uptake of serotonin.

Chemokines play an important role in immune and inflammatory responsesin various diseases and disorders, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis. These small secreted molecules are a growingsuperfamily of 8-14 kDa proteins characterised by a conserved fourcysteine motif. The chemokine superfamily can be divided into two maingroups exhibiting characteristic structural motifs, the Cys-X-Cys(C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basisof a single amino acid insertion between the NH-proximal pair ofcysteine residues and sequence similarity.

The C-X-C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

The C-C chemokines include potent chemoattractants of monocytes andlymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those previously mentioned.

In accordance with the present invention, there is therefore provided acompound of general formula

wherein,

-   -   R represents either a group    -   m is 0, 1, 2 or 3;    -   each R¹ independently represents halogen, cyano, nitro,        carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR⁹R¹⁰,        C₃-C₆ cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,        C₁-C₆ alkylcarbonylamino, sulphonamido (—SO₂NH₂), C₁-C₆        alkylsulphonyl, —C(O)NR¹¹R¹², —NR¹³C(O)—(NH)_(p)R¹⁴, phenyl, or        C₁-C₆ alkyl optionally substituted by carboxyl or C₁-C₆        alkoxycarbonyl;    -   p is 0 or 1;    -   X represents an oxygen or sulphur atom or a CH₂, CH(CH₃), OCH₂,        CH₂O, CH₂NH, NH or carbonyl group and Y represents a nitrogen        atom or a CH or C(OH) group, provided that when X represents an        oxygen or sulphur atom or a CH₂O, CH₂NH or NH group, then Y        represents a CH group;    -   Z¹ represents a bond or a group (CH₂)_(q) where q is 1 or 2;    -   Z² represents a bond or a group CH₂, with the proviso that Z¹        and Z² do not both simultaneously represent a bond;    -   Q represents an oxygen or sulphur atom or a group CH₂ or NH;    -   R² represents a group    -   n is 0, 1 or 2;    -   each R³ independently represents a C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, —CH₂OH or carboxyl group;    -   R⁴, R⁵, R⁶ and R⁷ each independently represent a hydrogen atom        or a C₁-C₆ alkyl group, or R⁴, R⁵, R⁶ and R⁷ together represent        a C₁-C₄ alkylene chain linking the two carbon atoms to which        they are attached to form a 4- to 7-membered saturated        carbocycle, or R⁵, R⁶ and R⁷ each represent a hydrogen atom and        R⁴ and R⁸ together with the carbon atoms to which they are        attached form a 5- to 6-membered saturated carbocycle;    -   R⁸ represents a hydrogen atom, a C₁-C₆ alkyl group or is linked        to R⁴ as defined above;    -   R⁹ and R¹⁰ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R⁹ and R¹⁰ together with the nitrogen atom        to which they are attached form a 4- to 7-membered saturated        heterocycle;    -   R¹¹ and R¹² each independently represent a hydrogen atom or a        C₁-C₆ alkyl group optionally substituted by C₁-C₆        alkoxycarbonyl;    -   R¹³ represents a hydrogen atom or a C₁-C₆ alkyl group;    -   R¹⁴ represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆        alkoxycarbonyl;    -   R¹⁵ represents carboxyl, C₁-C₆ alkylcarbonyl, C₁-C₆        alkoxycarbonyl, C₁-C₆ alkoxycarbonylC₁-C₆ alkyl or a group        —NR¹⁷R¹⁸, —NHSO₂CH₃, —NHC(O)CH₃, —C(O)NR¹⁷R¹⁸, —NHC(O)NR¹⁷R¹⁸,        —OC(O)NR¹⁷R¹⁸, —OCH₂C(O)NR¹⁷R¹⁸, —NHC(O)OR^(17′) or —OR^(17″);    -   t is 0, 1, 2 or 3;    -   each R¹⁶ independently represents halogen, cyano, nitro,        carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR¹⁹R²⁰,        C₃-C₆ cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,        C₁-C₆ alkylcarbonylamino, sulphonamido (—SO₂NH₂), C₁-C₆        alkylsulphonyl, —C(O)NR²¹R²², —NR²³C(O)(NH)_(v)R²⁴, phenyl, or        C₁-C₆ alkyl optionally substituted by carboxyl or C₁-C₆        alkoxycarbonyl;    -   R¹⁷ and R¹⁸ each independently represent (i) a hydrogen        atom, (ii) a 5- to 6-membered saturated or unsaturated ring        which may comprise at least one heteroatom chosen from nitrogen,        oxygen and sulphur, the ring being optionally substituted with        at least one substituent selected from halogen, methyl and        trifluoromethyl, or (iii) a C₁-C₆ alkyl group optionally        substituted by at least one substituent selected from halogen,        trifluoromethyl, carboxyl, C₁-C₆ alkoxycarbonyl and a 5- to        6-membered saturated or unsaturated ring which may comprise at        least one heteroatom chosen from nitrogen, oxygen and sulphur,        the ring being optionally substituted with at least one        substituent selected from halogen, methyl and trifluoromethyl,        or    -   R¹⁷ and R¹⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered saturated heterocycle;    -   R^(17′) represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl or C₁-C₆ alkoxycarbonyl;    -   R^(17″) is defined as for R¹⁷ above except that R^(17″) does not        represent a hydrogen atom;    -   R¹⁹ and R²⁰ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R¹⁹ and R²⁰ together with the nitrogen        atom to which they are attached form a 4- to 7-membered        saturated heterocycle;    -   R²¹ and R²² each independently represent a hydrogen atom or a        C₁-C₆ alkyl group optionally substituted by C₁-C₆        alkoxycarbonyl;    -   v is 0 or 1;    -   R²³ represents a hydrogen atom or a C₁-C₆ alkyl group; and    -   R²⁴ represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆        alkoxycarbonyl;        provided that when X is an oxygen atom or a group CH₂, Y is CH,        Z¹ and Z² each represent a group CH₂ and Q is an oxygen atom,        then R² is other than an unsubstituted indolyl group;        or a pharmaceutically acceptable salt or solvate thereof.

In the context of the present specification, an alkyl substituent groupor an alkyl moiety in a substituent group may be linear or branched.

In one aspect of the present invention, there is provided a compound ofgeneral formula

-   -   m is 0, 1, 2 or 3;    -   each R¹ independently represents halogen, cyano, nitro,        carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR⁹R¹⁰,        C₃-C₆ cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,        C₁-C₆ alkylcarbonylamino, sulphonamido, C₁-C₆ alkylsulphonyl,        —C(O)NR¹¹R¹², —NR¹³C(O)—(NH)_(p)R¹⁴, phenyl, or C₁-C₆ alkyl        optionally substituted by carboxyl or C₁-C₆ alkoxycarbonyl;    -   p is 0 or 1;    -   X represents an oxygen or sulphur atom or a CH₂, CH(CH₃), OCH₂,        CH₂O, CH₂NH, NH or carbonyl group and Y represents a nitrogen        atom or a CH or C(OH) group, provided that when X represents an        oxygen or sulphur atom or a CH₂O, CH₂NH or NH group, then Y        represents a CH group;    -   Z¹ represents a bond or a group (CH₂)_(q) where q is 1 or 2;    -   Z² represents a bond or a group CH₂, with the proviso that Z¹        and Z² do not both simultaneously represent a bond;    -   Q represents an oxygen or sulphur atom or a group CH₂ or NH;    -   R² represents a group    -   n is 0, 1 or 2;    -   each R³ independently represents a C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, —CH₂OH or carboxyl group;    -   R⁴, R⁵, R⁶ and R⁷ each independently represent a hydrogen atom        or a C₁-C₆ alkyl group, or R⁴, R⁵, R⁶ and R⁷ together represent        a C₁-C₄ alkylene chain linking the two carbon atoms to which        they are attached to form a 4- to 7-membered saturated        carbocycle, or R⁵, R⁶ and R⁷ each represent a hydrogen atom and        R⁴ and R⁸ together with the carbon atoms to which they are        attached form a 5- to 6-membered saturated carbocycle;    -   R⁸ represents a hydrogen atom, a C₁-C₆ alkyl group or is linked        to R⁴ as defined above;    -   R⁹ and R¹⁰ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R⁹ and R¹⁰ together with the nitrogen atom        to which they are attached form a 4- to 7-membered saturated        heterocycle;    -   R¹¹ and R¹² each independently represent a hydrogen atom or a        C₁-C₆ alkyl group optionally substituted by C₁-C₆        alkoxycarbonyl;    -   R¹³ represents a hydrogen atom or a C₁-C₆ alkyl group;    -   R¹⁴ represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆        alkoxycarbonyl;    -   R¹⁵ represents carboxyl, C₁-C₆ alkylcarbonyl, C₁-C₆        alkoxycarbonyl, C₁-C₆ alkoxycarbonylC₁-C₆ alkyl or a group        —NR¹⁷R¹⁸, —NHSO₂CH₃, —NHC(O)CH₃, —C(O)NR¹⁷R¹⁸, —NHC(O)NR¹⁷R¹⁸,        —OC(O)NR¹⁷R¹⁸, —OCH₂C(O)NR¹⁷R¹⁸, —NHC(O)OR^(17′) or —OR^(17″);    -   t is 0, 1, 2 or 3;    -   each R¹⁶ independently represents halogen, cyano, nitro,        carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR¹⁹R²⁰,        C₃-C₆ cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,        C₁-C₆ alkylcarbonylamino, sulphonamido (—SO₂NH₂), C₁-C₆        alkylsulphonyl, —C(O)NR²¹R²², —NR²³C(O)(NH)_(v)R²⁴, phenyl, or        C₁-C₆ alkyl optionally substituted by carboxyl or C₁-C₆        alkoxycarbonyl;    -   R¹⁷ and R¹⁸ each independently represent (i) a hydrogen        atom, (ii) a 5- to 6-membered saturated or unsaturated ring        which may comprise at least one heteroatom chosen from nitrogen,        oxygen and sulphur, the ring being optionally substituted with        at least one substituent selected from halogen, methyl and        trifluoromethyl, or (iii) a C₁-C₆ alkyl group optionally        substituted by at least one substituent selected from halogen,        trifluoromethyl, carboxyl, C₁-C₆ alkoxycarbonyl and a 5- to        6-membered saturated or unsaturated ring which may comprise at        least one heteroatom chosen from nitrogen, oxygen and sulphur,        the ring being optionally substituted with at least one        substituent selected from halogen, methyl and trifluoromethyl,        or    -   R¹⁷ and R¹⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered saturated heterocycle;    -   R^(17′) represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl or C₁-C₆ alkoxycarbonyl;    -   R^(17″) is defined as for R¹⁷ above except that R^(17″) does not        represent a hydrogen atom;    -   R¹⁹ and R²⁰ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R¹⁹ and R²⁰ together with the nitrogen        atom to which they are attached form a 4- to 7-membered        saturated heterocycle;    -   R²¹ and R²² each independently represent a hydrogen atom or a        C₁-C₆ alkyl group optionally substituted by C₁-C₆        alkoxycarbonyl;    -   v is 0 or 1;    -   R²³ represents a hydrogen atom or a C₁-C₆ alkyl group; and    -   R²⁴ represents a hydrogen atom, or a C₁-C₆ allyl group        optionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆        alkoxycarbonyl;        or a pharmaceutically acceptable salt or solvate thereof.

In another aspect of the invention, there is provided a compound ofgeneral formula

wherein,

-   -   R represents a group    -   m is 0, 1, 2 or 3;    -   each R¹ independently represents halogen, cyano, nitro,        carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR⁹R¹⁰,        C₃-C₆ cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,        C₁-C₆ alkylcarbonylamino, sulphonamido, C₁-C₆ alkylsulphonyl,        —C(O)NR¹¹R¹², —NR¹³C(O)—(NH)_(p)R¹⁴, phenyl, or C₁-C₆ alkyl        optionally substituted by carboxyl or C₁-C₆ alkoxycarbonyl;    -   p is 0 or 1;    -   X represents an oxygen or sulphur atom or a CH₂, CH(CH₃), OCH₂,        CH₂O, CH₂NH, NH or carbonyl group and Y represents a nitrogen        atom or a CH or C(OH) group, provided that when X represents an        oxygen or sulphur atom or a CH₂O, CH₂NH or NH group, then Y        represents a CH group;    -   Z¹ represents a bond or a group (CH₂)_(q) where q is 1 or 2;    -   Z² represents a bond or a group CH₂, with the proviso that Z¹        and Z² do not both simultaneously represent a bond;    -   Q represents an oxygen or sulphur atom or a group CH₂ or NH;    -   R² represents a group    -   n is 0, 1 or 2;    -   each R³ independently represents a C₁-C₆ alkyl, C₁-C₆        alkoxycarbonyl, —CH₂OH or carboxyl group;    -   R⁴, R⁵, R⁶ and R⁷ each independently represent a hydrogen atom        or a C₁-C₆ alkyl group, or R⁴, R⁵, R⁶ and R⁷ together represent        a C₁-C₄ alkylene chain linking the two carbon atoms to which        they are attached to form a 4- to 7-membered saturated        carbocycle, or R⁵, R⁶ and R⁷ each represent a hydrogen atom and        R⁴ and R⁸ together with the carbon atoms to which they are        attached form a 5- to 6-membered saturated carbocycle;    -   R⁸ represents a hydrogen atom, a C₁-C₆ alkyl group or is linked        to R⁴ as defined above;    -   R⁹ and R¹⁰ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R⁹ and R¹⁰ together with the nitrogen atom        to which they are attached form a 4- to 7-membered saturated        heterocycle;    -   R¹¹ and R¹² each independently represent a hydrogen atom or a        C₁-C₆ alkyl group optionally substituted by C₁-C₆        alkoxycarbonyl;    -   R¹³ represents a hydrogen atom or a C₁-C₆ alkyl group; and    -   R¹⁴ represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆        alkoxycarbonyl;        provided that when X is an oxygen atom or a group CH₂, Y is CH,        Z¹ and Z² each represent a group CH₂ and Q is an oxygen atom,        then R² is other than an unsubstituted indolyl group;        or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect of the invention, there is provided a compound ofgeneral formula

-   -   m is 0, 1, 2 or 3;    -   each R¹ independently represents halogen, cyano, nitro,        carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR⁹R¹⁰,        C₃-C₆ cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,        C₁-C₆ alkylcarbonylamino, sulphonamido, C₁-C₆ alkylsulphonyl,        —C(O)NR¹¹R¹², —NR¹³C(O)—(NH)_(p)R¹⁴, phenyl, or C₁-C₆ alkyl        optionally substituted by carboxyl or C₁-C₆ alkoxycarbonyl;    -   p is 0 or 1;    -   Q represents an oxygen or sulphur atom or a group CH₂ or NH;    -   R² represents a group    -   R⁴, R⁵, R⁶ and R⁷ each independently represent a hydrogen atom        or a C₁-C₆ alkyl group, or R⁴, R⁵, R⁶ and R⁷ together represent        a C₁-C₄ alkylene chain linking the two carbon atoms to which        they are attached to form a 4- to 7-membered saturated        carbocycle, or R⁵, R⁶ and R⁷ each represent a hydrogen atom and        R⁴ and R⁸ together with the carbon atoms to which they are        attached form a 5- to 6-membered saturated carbocycle;    -   R⁸ represents a hydrogen atom, a C₁-C₆ alkyl group or is linked        to R⁴ as defined above;    -   R⁹ and R¹⁰ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R⁹ and R¹⁰ together with the nitrogen atom        to which they are attached form a 4- to 7-membered saturated        heterocycle;    -   R¹¹ and R¹² each independently represent a hydrogen atom or a        C₁-C₆ alkyl group optionally substituted by C₁-C₆        alkoxycarbonyl;    -   R¹³ represents a hydrogen atom or a C₁-C₆ alkyl group;    -   R¹⁴ represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆        alkoxycarbonyl;    -   R¹⁵ represents carboxyl, C₁-C₆ alkylcarbonyl, C₁-C₆        alkoxycarbonyl, C₁-C₆ alkoxycarbonylC₁-C₆ alkyl or a group        —NR¹⁷R¹⁸, —NHSO₂CH₃, —NHC(O)CH₃, —C(O)NR¹⁷R¹⁸, —NHC(O)NR¹⁷R¹⁸,        —OC(O)NR¹⁷R¹⁸, —OCH₂C(O)NR¹⁷R¹⁸, —NHC(O)OR^(17′) or —OR^(17″);    -   t is 0, 1, 2 or 3;    -   each R¹⁶ independently represents halogen, cyano, nitro,        carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR¹⁹R²⁰,        C₃-C₆ cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,        C₁-C₆ alkylcarbonylamino, sulphonamido (—SO₂NH₂), C₁-C₆        alkylsulphonyl, —C(O)NR²¹R²², —NR²³C(O)(NH)_(v)R²⁴, phenyl, or        C₁-C₆ alkyl optionally substituted by carboxyl or C₁-C₆        alkoxycarbonyl;    -   R¹⁷ and R¹⁸ each independently represent (i) a hydrogen        atom, (ii) a 5- to 6-membered saturated or unsaturated ring        which may comprise at least one heteroatom chosen from nitrogen,        oxygen and sulphur, the ring being optionally substituted with        at least one substituent selected from halogen, methyl and        trifluoromethyl, or (iii) a C₁-C₆ alkyl group optionally        substituted by at least one substituent selected from halogen,        trifluoromethyl, carboxyl, C₁-C₆ alkoxycarbonyl and a 5- to        6-membered saturated or unsaturated ring which may comprise at        least one heteroatom chosen from nitrogen, oxygen and sulphur,        the ring being optionally substituted with at least one        substituent selected from halogen, methyl and trifluoromethyl,        or    -   R¹⁷ and R¹⁸ together with the nitrogen atom to which they are        attached form a 4- to 7-membered saturated heterocycle;    -   R^(17′) represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl or C₁-C₆ alkoxycarbonyl;    -   R^(17″) is defined as for R¹⁷ above except that R^(17″) does not        represent a hydrogen atom;    -   R¹⁹ and R²⁰ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group, or R¹⁹ and R²⁰ together with the nitrogen        atom to which they are attached form a 4- to 7-membered        saturated heterocycle;    -   R²¹ and R²² each independently represent a hydrogen atom or a        C₁-C₆ alkyl group optionally substituted by C₁-C₆        alkoxycarbonyl;    -   v is 0 or 1;    -   R²³ represents a hydrogen atom or a C₁-C₆ alkyl group; and    -   R²⁴ represents a hydrogen atom, or a C₁-C₆ alkyl group        optionally substituted by carboxyl, C₁-C₆ alkoxy or C₁-C₆        alkoxycarbonyl;        or a pharmaceutically acceptable salt or solvate thereof.

The integer m is preferably 0, 1 or 2.

Each R¹ independently represents halogen (e.g. chlorine, fluorine,bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C₃-C₆ cycloalkyl(cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C₁-C₆, preferablyC₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl), C₁-C₆, preferably C₁-C₄, haloalkyl (e.g.trifluoromethyl), C₁-C₆, preferably C₁-C₄, haloalkoxy (e.g.trifluoromethoxy), —NR⁹R¹⁰, C₃-C₆ cycloalkylamino (e.g.cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino),C₁-C₆, preferably C₁-C₄, alkylthio (e.g. methylthio or ethylthio),C₁-C₆, preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,n-pentylcarbonyl or n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄,alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino),sulphonamido, C₁-C₆, preferably C₁-C₄, alkylsulphonyl (e.g.methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl,n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), —C(O)NR¹¹R¹²,—NR¹³C(O)—(NH)_(p)R¹⁴, phenyl, or C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl) optionally substituted by carboxyl or C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl).

Most preferably, each R¹ independently represents halogen (particularlychlorine or fluorine), cyano, nitro, C₁-C₆ alkoxy (especially methoxy),C₁-C₆ alkylcarbonyl (especially methylcarbonyl) or C₁-C₆alkylcarbonylamino (particularly methylcarbonylamino).

Preferably X represents an oxygen atom or a CH₂, OCH₂, CH₂O, NH orcarbonyl group.

Preferably Y represents a nitrogen atom or CH group.

Preferred combinations of X—Y include O—CH, OCH₂—CH, NH—CH, CH₂O—CH,CH₂—N, C(O)—N and CH₂—CCH.

Preferred combinations of Y, Z¹ and Z² include:

Y Z¹ Z² CH CH₂ bond CH bond CH₂ CH CH₂ CH₂ CH (CH₂)₂ bond N CH₂ CH₂

Q preferably represents an oxygen atom.

Each R³ independently represents a C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl), C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (e.g.methoxycarbonyl or ethoxycarbonyl), —CH₂OH or carboxyl group. It ispreferred that R³ represents a methyl, methoxycarbonyl, ethoxycarbonyl,—CH₂OH or carboxyl group.

R⁴, R⁵, R⁶ and R⁷ each independently represent a hydrogen atom or aC₁-C₆, preferably C₁-C₄, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R⁴, R⁵, R⁶ andR⁷ together represent a C₁-C₄ alkylene chain linking the two carbonatoms to which they are attached to form a 4- to 7-membered saturatedcarbocycle (e.g. cyclohexyl or preferably cyclopentyl), or R⁵, R⁶ and R⁷each represent a hydrogen atom and R⁴ and R⁸ together with the carbonatoms to which they are attached form a 5- to 6-membered saturatedcarbocycle (preferably cyclopentyl).

R⁸ represents a hydrogen atom, a C₁-C₆, preferably C₁-C₄, alkyl group(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl) or is linked to R⁴ as defined above.

R⁹ and R¹⁰ each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R⁹ and R¹⁰together with the nitrogen atom to which they are attached form a 4- to7-membered saturated heterocycle (preferably pyrrolidinyl orpiperidinyl).

R¹¹ and R¹² each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionallysubstituted by a C₁-C₆, preferably C₁-C₄, alkoxycarbonyl substituentgroup.

R¹³ represents a hydrogen atom or a C₁-C₆, preferably C₁-C₄, alkyl group(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl).

R¹⁴ represents a hydrogen atom, or a C₁-C₆, preferably C₁-C₄, alkylgroup (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl,C₁-C₆, preferably C₁-C₄, alkoxy or C₁-C₆, preferably C₁-C₄,alkoxycarbonyl.

R¹⁵ represents carboxyl, C₁-C₆, preferably C₁-C₄, alkylcarbonyl (e.g.methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl,n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C₁-C₆, preferablyC₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), C₁-C₆alkoxycarbonylC₁-C₆ alkyl, preferably C₁-C₄ alkoxycarbonylC₁-C₄ alkyl(e.g. methoxycarbonylmethyl or methoxycarbonylethyl), or a group—NR¹⁷R¹⁸, —NHSO₂CH₃, —NHC(O)CH₃, —C(O)NR¹⁷R¹⁸, —NHC(O)NR¹⁷R¹⁸,—OC(O)NR¹⁷R¹⁸, —OCH₂C(O)NR¹⁷R¹⁸, —NHC(O)OR^(17′) or —OR^(17″).

It is preferred that R¹⁵ represents C₁-C₄ alkoxy (especially methoxy),C₁-C₄ alkylcarbonyl (especially methylcarbonyl or ethylcarbonyl), C₁-C₄alkoxycarbonylC₁-C₄ alkyl (particularly methoxycarbonylmethyl ormethoxycarbonylethyl), —NHC(O)CH₃, —C(O)NR¹⁷R¹⁸, —NHSO₂CH₃ or—NHC(O)NR¹⁷R¹⁸.

Each R¹⁶ independently represents halogen (e.g. chlorine, fluorine,bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C₃-C₆ cycloalkyl(cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C₁-C₆, preferablyC₁-C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl), C₁-C₆, preferably C₁-C₄, haloalkyl (e.g.trifluoromethyl), C₁-C₆, preferably C₁-C₄, haloalkoxy (e.g.trifluoromethoxy), —NR¹⁹R²⁰, C₃-C₆ cycloalkylamino (e.g.cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino),C₁-C₆, preferably C₁-C₄, alkylthio (e.g. methylthio or ethylthio),C₁-C₆, preferably C₁-C₄, alkylcarbonyl (e.g. methylcarbonyl,ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl,n-pentylcarbonyl or n-hexylcarbonyl), C₁-C₆, preferably C₁-C₄,alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino),sulphonamido, C₁-C₆, preferably C₁-C₄, alkylsulphonyl (e.g.methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl,n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), —C(O)NR²¹R²²,—NR²³C(O)—(NH)_(v)R²⁴, phenyl, or C₁-C₆, preferably C₁-C₄, alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl) optionally substituted by carboxyl or C₁-C₆,preferably C₁-C₄, alkoxycarbonyl (e.g. methoxycarbonyl orethoxycarbonyl).

Preferably, each R¹⁶ independently represents halogen (particularlychlorine or fluorine), hydroxyl, cyano, C₁-C₄ alkoxy (especiallymethoxy), C₁-C₄ alkoxycarbonyl (especially methoxycarbonyl), C₁-C₄haloalkyl (especially trifluoromethyl), C₁-C₄ alkylcarbonyl(particularly methylcarbonyl), phenyl or C₁-C₄ alkyl (e.g. methyl ortert-butyl).

R¹⁷ and R¹⁸ each independently represent (i) a hydrogen atom, (ii) a 5-to 6-membered saturated or unsaturated ring which may comprise at leastone heteroatom (e.g. one, two or three heteroatoms independently) chosenfrom nitrogen, oxygen and sulphur (such as cyclopentyl, cyclohexyl,pyrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,thienyl or furanyl), the ring being optionally substituted with at leastone substituent (e.g. one, two or three substituents independently)selected from halogen (e.g. fluorine, chlorine, bromine or iodine),methyl and trifluoromethyl, or (iii) a C₁-C₆, preferably C₁-C₄, alkylgroup (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl) optionally substituted by at least onesubstituent (e.g. one, two or three substituents independently) selectedfrom halogen (e.g. fluorine, chlorine, bromine or iodine),trifluoromethyl, carboxyl, C₁-C₆, preferably C₁-C₄, alkoxycarbonyl,especially methoxycarbonyl, and a 5- to 6-membered saturated orunsaturated ring which may comprise at least one heteroatom (e.g. one,two or three heteroatoms independently) chosen from nitrogen, oxygen andsulphur (such as cyclopentyl, cyclohexyl, pyrolyl, imidazolyl,pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl or furanyl), thering being optionally substituted with at least one substituent (e.g.one, two or three substituents independently) selected from halogen(e.g. fluorine, chlorine, bromine or iodine), methyl andtrifluoromethyl, or

R¹⁷ and R¹⁸ together with the nitrogen atom to which they are attachedform a 4- to 7-membered saturated heterocycle (preferably pyrrolidinylor piperidinyl).

R^(17′) represents a hydrogen atom or a C₁-C₆, preferably C₁-C₄, alkylgroup (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or,more preferably, C₁-C₆, preferably C₁-C₄, alkoxycarbonyl, especiallymethoxycarbonyl,

R¹⁹ and R²⁰ each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R¹⁹ and R²⁰together with the nitrogen atom to which they are attached form a 4- to7-membered saturated heterocycle (preferably pyrrolidinyl orpiperidinyl).

R²¹ and R²² each independently represent a hydrogen atom or a C₁-C₆,preferably C₁-C₄, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionallysubstituted by a C₁-C₆, preferably C₁-C₄, alkoxycarbonyl substituentgroup.

R²³ represents a hydrogen atom or a C₁-C₆, preferably C₁-C₄, alkyl group(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,-isobutyl, tert-butyl,n-pentyl or n-hexyl).

R²⁴ represents a hydrogen atom, or a C₁-C₆, preferably C₁-C₄, alkylgroup (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl,C₁-C₆, preferably C₁-C₄, alkoxy or C₁-C₆, preferably C₁-C₄,alkoxycarbonyl.

Preferred compounds of the invention include:

-   -   N-(2-{3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy-propoxy}-phenyl)-acetamide        hydrochloride,    -   N-(5-Chloro-2-{3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy-propoxy}-phenyl)-acetamide        hydrochloride,    -   N-(2-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)-acetamide,    -   1-(2-Aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol        dihydrochloride,    -   N-(2-{3-[3-(3,4-dichlorophenoxy)-1-pyrrolidinyl)-2-hydroxypropoxy}phenyl)-acetamide        hydrochloride,    -   2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoic        acid methyl ester,    -   2-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionic        acid methyl ester,    -   N-[2-({(1R,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopentyl}oxy)phenyl]acetamide,    -   N-[2-({(1S,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopentyl}oxy)phenyl]acetamide,    -   N-[2-({(2,3-trans)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclohexyl}oxy)phenyl]acetamide,    -   N-(5-Chloro-2-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(3-Acetyl-2-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-fluoro-phenyl)-acetamide,    -   1-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol,    -   1-(7-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,    -   N-(4-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide,    -   N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl)-acetamide,    -   N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(5-Chloro-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(3-Acetyl-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-fluoro-phenyl)-acetamide,    -   1-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol,    -   1-(7-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,    -   N-(4-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide,    -   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl)-acetamide,    -   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide    -   N-(5-Chloro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(3-Acetyl-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide,    -   N-(5-Fluoro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   1-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol,    -   1-(7-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,    -   N-(4-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide,    -   N-(4-Fluoro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(5-Chloro-2-{3-[3-(3,4-difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(3-Acetyl-2-{3-[3-(3,4-difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-fluoro-phenyl)-acetamide,    -   1-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol,    -   1-(7-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,    -   N-(4-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide,    -   N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl)-acetamide,    -   N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(5-Chloro-2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(3-Acetyl-2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide,    -   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-fluoro-phenyl)-acetamide,    -   1-(7-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,    -   N-(4-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide,    -   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl)-acetamide,    -   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(5-Chloro-2-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(3-Acetyl-2-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide,    -   N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-fluoro-phenyl)-acetamide,    -   1-(7-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,    -   N-(4-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide,    -   N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl)-acetamide,    -   N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide,    -   N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-{5-Chloro-2-[3-(8-chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide,    -   N-{3-Acetyl-2-[3-(8-chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5-methyl-phenyl}-acetamide,    -   N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4-methyl-phenyl}-acetamide,    -   N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5-fluoro-phenyl}-acetamide,    -   1-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-3-(1H-indol-7-yloxy)-propan-2-ol,    -   1-{7-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-indol-1-yl}-ethanone,    -   N-{4-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-biphenyl-3-yl}-acetamide,    -   N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4-fluoro-phenyl}-acetamide,    -   N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5-methyl-phenyl}-acetamide,    -   N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide,    -   N-{5-Chloro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide,    -   N-{3-Acetyl-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5-methyl-phenyl}-acetamide,    -   N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4-methyl-phenyl}-acetamide,    -   N-{5-Fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide,    -   1-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-3-(1H-indol-7-yloxy)-propan-2-ol,    -   1-{7-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-indol-1-yl}-ethanone,    -   N-{4-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-biphenyl-3-yl}-acetamide,    -   N-{4-Fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide,    -   N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5-methyl-phenyl}-acetamide,    -   N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide,    -   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   3-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(2,6-dimethoxy-phenoxy)-propan-2-ol,    -   1-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol,    -   2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   1-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one,    -   1-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone,    -   3-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   1-(2,6-Dimethoxy-phenoxy)-3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-propan-2-ol,    -   1-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol,    -   (2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-acetic        acid methyl ester,    -   (2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-acetic        acid methyl ester,    -   2-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionic        acid methyl ester,    -   2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   1-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone,    -   1-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one,    -   1-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone,    -   N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4-methylphenyl]acetamide,    -   3-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   1-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol,    -   (2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-acetic        acid methyl ester,    -   2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   1-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone,    -   1-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one,    -   1-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone,    -   N-(2-{3-[4-(3,4-dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   3-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   1-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-3-(2,6-dimethoxy-phenoxy)-propan-2-ol,    -   1-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol,    -   (2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-acetic        acid methyl ester,    -   2-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionic        acid methyl ester,    -   2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   1-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone,    -   1-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one,    -   1-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone,    -   N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   3-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   (2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-acetic        acid methyl ester,    -   2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   4-{1-[2-Hydroxy-3-(2-propionyl-phenoxy)-propyl]-pyrrolidin-3-yloxy}-benzonitrile,    -   N-(2-{2-Hydroxy-3-[3-(4-methoxy-phenoxy)-pyrrolidin-1-yl]-propoxy}-phenyl)-acetamide,    -   N-(4-chloro-2-{3-[4-(3,4-dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   3-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   1-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol,    -   (2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-acetic        acid methyl ester,    -   2-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionic        acid methyl ester,    -   2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   1-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone,    -   1-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one,    -   1-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone,    -   N-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   3-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   1-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one,    -   (2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-acetic        acid methyl ester,    -   N-(2-{3-[3-(3,4-Difluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   3-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   1-(2,6-Dimethoxy-phenoxy)-3-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-propan-2-ol,    -   1-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol,    -   1-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone,    -   2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   1-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one,    -   (2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-acetic        acid methyl ester,    -   N-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   3-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   1-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol,    -   1-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone,    -   2-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionic        acid methyl ester,    -   2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   1-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone,    -   N-(2-{3-[4-(4-Acetylamino-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(4-{1-[3-(2-Acetyl-phenoxy)-2-hydroxy-propyl]-piperidin-4-yloxy}-phenyl)-acetamide,    -   N-(4-cyano-2-{3-[4-(3,4-dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   3-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   1-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol,    -   1-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone,    -   2-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionic        acid methyl ester,    -   2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   1-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone,    -   1-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one,    -   (2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-acetic        acid methyl ester,    -   N-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   3-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionic        acid methyl ester,    -   1-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone,    -   2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide,    -   1-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one,    -   N-[2-({(1R,2R)-2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-1-hydroxycyclopentyl}methoxy)phenyl]acetamide,    -   Methyl        (2S,4R)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-[(4-chlorobenzyl)oxy]-2-pyrrolidinecarboxylate        hydrochloride,    -   N-(2-{3-[4-(3,4-Dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide,    -   N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(4-Chloro-2-{3-[4-(4-chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)-acetamide,    -   N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-cyanophenyl)acetamide,    -   N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide,    -   N-(5-Chloro-2-{3-[4-(4-fluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(5-Chloro-2-{3-[4-(3,4-difluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(5-Cyano-2-{3-[4-(4-fluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}-phenyl)acetamide,    -   N-(5-Cyano-2-{3-[4-(3,4-difluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(2-{3-[4-(4-Fluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide,    -   N-(2-{3-[4-(3,4-Difluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide,    -   N-(2-{3-[3(S)-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-(R)-hydroxy-propoxy-phenyl)acetamide,    -   N-(2-{3-[3S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2S-hydroxy-propoxy}-phenyl)-acetamide        hydrochloride,    -   N-(2-{3-[3(R)-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-(S)-hydroxy-propoxy-phenyl)acetamide,    -   N-[5-Chloro-2-({(2S)-3-[(3S)-3-(4-chloro-phenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide,    -   N-[5-Chloro-2-({(2R)-3-[(3R)-3-(4-chloro-phenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide,    -   N-[5-Chloro-2-({(2S)-3-[(3R)-3-(4-chloro-phenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide,    -   N-[5-Chloro-2-({(2R)-3-[(3S)-3-(4-chloro-phenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide,    -   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4,5-difluoro-phenyl)-acetamide,    -   N-{5-Chloro-2-[2-hydroxy-3-(3-phenoxy-pyrrolidin-1-yl)-propoxy]-phenyl}-acetamide,    -   N-(5-Chloro-2-{2-hydroxy-3-[3-(4-nitro-phenoxy)-pyrrolidin-1-yl]-propoxy}-phenyl)-acetamide,    -   N-(5-Acetyl-2-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   4-Acetylamino-3-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoic        acid methyl ester,    -   N-(3-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-naphthalen-2-yl)-acetamide,    -   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-cyano-phenyl)-acetamide,    -   4-Acetylamino-3-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoic        acid methyl ester,    -   N-(3-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-naphthalen-2-yl)-acetamide,    -   N-(5-Cyano-2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-trifluoromethyl-phenyl)-acetamide,    -   N-(5-Chloro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide        trifluoroacetate,    -   N-(5-Acetyl-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide        trifluoroacetate,    -   N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-methanesulfonamide,    -   N-(5-Chloro-2-[3-[3,4-dichlorophenoxy)-1-pyrrodinyl]-2-hydroxypropoxy]-phenyl)urea,    -   1-(3-{2-[(Aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(4-chlorophenoxy)pyrrolidinium        2,2,2-trifluoroacetate,    -   1-(3-{2-[(Aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(3,4-dichlorophenoxy)pyrrolidinium        2,2,2-trifluoroacetate,    -   1-(3-{2-[(Aminocarbonyl)amino]-4-chlorophenoxy}-2-hydroxypropyl)-3-(4-chlorophenoxy)pyrrolidinium        2,2,2-trifluoroacetate,    -   N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N′-ethylurea        hydrochloride,    -   N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N′-methylurea        hydrochloride,    -   (2S,4S)-1-{3-[2-(Acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylic        acid; compound with trifluoroacetic acid,    -   Ethyl        (2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(3,4-dichlorophenoxy)-2-pyrrolidinecarboxylate;        trifluoroacetic acid salt,    -   N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide;        trifluoroacetic acid salt,    -   N-[2-({(2R)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide;        trifluoroacetic acid salt,    -   N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxy-2-methylpropoxy}phenyl)acetamide        hydrochloride,    -   N-(2-{(1S*,2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide,    -   N-(2-{(1R*,2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide,    -   N-(2-{(2R*,3R*)-3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-butoxy}-phenyl)-acetamide,    -   N-(2-{(1S*,2R*,3S*)-3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide,    -   N-(2-{(2R*,3S*)-3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-butoxy}-phenyl)-acetamide,    -   N-(2-{(2R*,3R*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-butoxy}-phenyl)-acetamide,    -   N-(2-{(2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-butoxy}-phenyl)-acetamide,    -   N-(2-{(1S*,2R*,3S*)-3-[4-(3-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide,    -   N-[5-Chloro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide,    -   N-[4-Fluoro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide,    -   N-(2-{3-[4-(3,4-Dichlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}-phenyl)acetamide        dihydrochloride,    -   N-(2-{3-[4-(3,4-Dichlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}-4-fluorophenyl)acetamide,    -   N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(5-Chloro-2-{3-[4-(3,4-dichlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(5-Chloro-2-{3-[4-(3,4-dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide,    -   N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}-4-fluorophenyl)acetamide,    -   N-(2-{3[(S*R*)-4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(2-{3[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(5-Chloro-2-{3-[(S*R*)-4-(3,4-dichlorobenzyl)-2,5-dimethylpiperazinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(5-Chloro-2-{3-[(S*R*)-4-(4-chlorobenzyl)-2,5-dimethylpiperazinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   1-(5-Chloro-2-{3-[4-(4-chlorobenzoyl)-1-piperazinyl]-2-hydroxypropoxy}phenyl)-1-ethanone,    -   N-(5-Cyano-2-{3-[(S*R*)-4-(3,4-dichlorobenzyl)-2,5-dimethylpiperazinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(2-{3-[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethylpiperazinyl]-2-hydroxypropoxy}-5-cyanophenyl)acetamide,    -   N-(5-Chloro-2-{3-[4-(4-chlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}-phenyl)acetamide,    -   N-(4-Chloro-2-{3-[4-(4-chlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(2-{3-[4-(4-Chlorobenzoyl)-1-piperazinyl]-2-hydroxypropoxy}-5-cyanophenyl)acetamide,    -   N-(2-{3-[4-(4-Chlorobenzoyl)-1-piperazinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide,    -   N-[5-Chloro-2-({(1R,2S,3R)-3-[(3S)-3-(4-chlorophenoxy)pyrrolidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide,    -   N-{2-[(2S)-(3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-fluorophenyl}acetamide,    -   N-[2-({(2S)-3-[(3S)-3-(4-Chlorobenzyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide        hydrochloride,    -   N-(5-Chloro-2-{3-[3-(4-chloro-benzyl)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide        trifluoroacetic acid salt,    -   N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methylphenyl)-1-pyrrolidinecarboxamide        trifluoroacetate,    -   N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-hydroxyphenyl)acetamide        trifluoroacetate,    -   N-[2-({(2S)-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-fluorophenyl]acetamide        trifluoroacetic acid salt,    -   N-(2-(3-(4-Chloro-phenoxy)-pyrrolidin-1-yl)-2-hydroxy-propoxy)-4,6-difluoro-phenyl)-acetamide        hydrochloride,    -   N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)-4-fluorophenyl]acetamide        trifluoroacetic acid salt,    -   N-[2-({(2S)-3-[(3R)-3-(4-Chlorobenzyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide        hydrochloride,    -   N-{2-[(2R)-(3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-fluorophenyl}acetamide,    -   N-[2-({(2S)-3-[(2R,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide        trifluoroacetic acid salt,    -   N-{2-[(2S)-(3-{(3R)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-fluorophenyl}acetamide,    -   N′-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methylphenyl)-N,N-dimethylurea        trifluoroacetate,    -   N-(2-{3-[3-(4-Chloroanilino)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-{2-[(3-{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-1-methylpropyl)oxy]phenyl}acetamide        hydrochloride,    -   N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methoxyphenyl)acetamide        hydrochloride,    -   N-(2-[3-(4-Chloro-benzyloxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy)-phenyl)-acetamide        trifluoroacetic acid salt,    -   N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-acetamide,    -   N-(2-{(1S,2R,3S)*-3-[(3S)-3-(3,4-Difluoro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-cyclopentyloxy}-5-chloro-phenyl)-acetamide        (diastereomeric mixture),    -   N-[2-({(2R,3S)*-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxybutyl}oxy)-4-methylphenyl]acetamide        (diastereomeric mixture),    -   N-{2-[(3-{4-[(3,4-Dichlorophenyl)oxy]-1-piperidinyl}-2-hydroxy-2-methylpropyl)oxy]-4-fluorophenyl}acetamide        hydrochloride,    -   N-(2-{(1S,2R,3S)*-3-[(3S)-3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-4-fluoro-phenyl)-acetamide        (diastereomeric mixture),    -   N-(5-Chloro-2-{3-[3-(3,4-difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(5-Chloro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide,    -   N-(4-Cyano-2-{3-[4-(3,4-dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide,    -   N-(4-Hydroxy-2-{(1S,2R,3S)*-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide        (diastereomeric mixture),    -   N-(4-Hydroxy-2-{(1S,2R,3S)-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide,    -   N-(4-Hydroxy-2-{(1R,2S,3R)-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide,    -   N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide,    -   N-[2-({(1R,2S,3R)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide,    -   N-[5-Chloro-2-({(1S,2R,3S)-3-[(3S)-3-(4-chlorophenoxy)pyrrolidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide,    -   N-{5-Chloro-2-[((1S,2R,3S)*-3-{[1-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxycyclopentyl)oxy]phenyl}acetamide        (racemic mixture), and    -   N-[2-({(2S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxypropyl}-oxy)-4-hydroxyphenyl]acetamide.

The present invention further provides a process for the preparation ofa compound of formula (I) as defined above which comprises,

-   (a) reacting a compound of general formula    R—H  (II)    wherein R is as defined in formula (I), with a compound of general    formula    wherein Q, R², R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in formula (I);    or-   (b) reacting a compound of general formula    wherein R, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in formula (I), with    a compound of general formula    L¹-Q-R²  (V)    wherein L¹ represents a hydrogen atom or an activating group (e.g.    Li when Q is CH₂) and Q and R² are as defined in formula (I);    and optionally thereafter converting the compound of formula (I) to    a further compound of formula (I); and, if desired, forming a    pharmaceutically acceptable salt or solvate of the compound of    formula (I).

In one aspect, the invention provides a process for the preparation of acompound of formula (I′) as hereinbefore defined which comprises,

-   (a) reacting a compound of general formula    R—H  (II′)    wherein R is as defined in formula (I′), with a compound of general    formula    wherein Q, R², R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in formula (I′);    or-   (b) reacting a compound of general formula    wherein R, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in formula (I′),    with a compound of general formula    L¹-Q-R²  (V′)    wherein L¹ represents a hydrogen atom or an activating group (e.g.    Li when Q is CH₂) and Q and R² are as defined in formula (I′);    and optionally thereafter converting the compound of formula (I′) to    a further compound of formula (I′); and, if desired, forming a    pharmaceutically acceptable salt or solvate of the compound of    formula (I′).

In another aspect, the invention provides a process for the preparationof a compound of formula (I″) as hereinbefore defined which comprises,

-   (a) reacting a compound of general formula    R—H  (II″)    wherein R is as defined in formula (I″), with a compound of general    formula    wherein Q, R², R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in formula (I″);    or-   (b) reacting a compound of general formula    wherein R, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in formula (I″),    with a compound of general formula    L¹-Q-R²  (V″)    wherein L¹ represents a hydrogen atom or an activating group (e.g.    Li when Q is CH₂) and Q and R² are as defined in formula (I″);    and optionally thereafter converting the compound of formula (I″) to    a further compound of formula (I″); and, if desired, forming a    pharmaceutically acceptable salt or solvate of the compound of    formula (I″).

In yet another aspect, the invention provides a process for thepreparation of a compound of formula (I′″) as hereinbefore defined whichcomprises,

-   (a) reacting a compound of general formula    R—H  (II′″)    wherein R is as defined in formula (I′″), with a compound of general    formula    wherein Q, R², R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in formula    (I′″); or-   (b) reacting a compound of general formula    wherein R, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in formula (I′″),    with a compound of general formula    L¹-Q-R²  (V′″)    wherein L¹ represents a hydrogen atom or an activating group (e.g.    Li when Q is CH₂) and Q and R² are as defined in formula (I′″);    and optionally thereafter converting the compound of formula (I′″)    to a further compound of formula (I′″); and, if desired, forming a    pharmaceutically acceptable salt or solvate of the compound of    formula (I′″).

The processes of the invention may conveniently be carried out in asolvent, e.g. an organic solvent such as an alcohol (e.g. methanol orethanol), a hydrocarbon (e.g. toluene) or acetonitrile at a temperatureof, for example, 15° C. or above such as a temperature in the range from20 to 120° C.

Compounds of formulae (II), (II′), (II″), (II′″), (III), (III′), (III″),(III′″), (IV), (IV′), (IV″), (IV′″), (V), (V′), (V″) and (V′″) areeither commercially available, are well known in the literature or maybe prepared easily using known techniques.

Compounds of formula (I), (I′), (I″) or (I′″) can be converted intofurther compounds of formula (I), (I′), (I″) or (I′″) using standardprocedures. For example, a compound of formula (I) in which R¹⁵represents —NHC(O)CH₃ can be converted to a further compound of formula(I) in which R¹⁵ represents —NH₂ by a hydrolysis reaction in thepresence of hydrochloric acid.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I), (I′), (I″) or (I′″) may involve, at anappropriate stage, the removal of one or more protecting groups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (I), (I′), (I″) or (I′″) above may be convertedto a pharmaceutically acceptable salt or solvate thereof, preferably anacid addition salt such as a hydrochloride, hydrobromide, phosphate,acetate, fumarate, maleate, tartrate, citrate, oxalate,methanesulphonate or p-toluenesulphonate.

Compounds of formula (I), (I′), (I″) or (I′″) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses the use of all geometric and optical isomers of thecompounds of formula (I), (I′), (I″) or (I′″) and mixtures thereofincluding racemates. The use of tautomers and mixtures thereof also forman aspect of the present invention. Enantiomerically pure forms areparticularly desired.

The compounds of formula (I), (I′), (I″) or (I′″) have activity aspharmaceuticals, in particular as modulators of chemokine receptor(especially MIP-1α chemokine receptor) activity, and may be used in thetreatment of autoimmune, inflammatory, proliferative andhyperproliferative diseases and immunologically-mediated diseasesincluding rejection of transplanted organs or tissues and AcquiredImmunodeficiency Syndrome (AIDS).

Examples of these conditions are:

-   (1) (the respiratory tract) airways diseases including chronic    obstructive pulmonary disease (COPD) such as irreversible COPD;    asthma, such as bronchial, allergic, intrinsic, extrinsic and dust    asthma, particularly chronic or inveterate asthma (e.g. late asthma    and airways hyper-responsiveness); bronchitis; acute, allergic,    atrophic rhinitis and chronic rhinitis including rhinitis caseosa,    hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and    rhinitis medicamentosa; membranous rhinitis including croupous,    fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis;    seasonal rhinitis including rhinitis nervosa (hay fever) and    vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases,    fibroid lung and idiopathic interstitial pneumonia;-   (2) (bone and joints) rheumatoid arthritis, seronegative    spondyloarthropathies (including ankylosing spondylitis, psoriatic    arthritis and Reiter's disease), Behcet's disease, Sjogren's    syndrome and systemic sclerosis;-   (3) (skin) psoriasis, atopical dermatitis, contact dermatitis and    other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus,    Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria,    angiodermas, vasculitides, erythemas, cutaneous eosinophilias,    uveitis, Alopecia areata and vernal conjunctivitis;-   (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic    gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis,    food-related allergies which have effects remote from the gut, e.g.,    migraine, rhinitis and eczema;-   (5) (other tissues and systemic disease) multiple sclerosis,    atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus    erythematosus, systemic lupus, erythematosus, Hashimoto's    thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome,    eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy,    sezary syndrome and idiopathic thrombocytopenia pupura;-   (6) (allograft rejection) acute and chronic following, for example,    transplantation of kidney, heart, liver, lung, bone marrow, skin and    cornea; and chronic graft versus host disease;-   (7) cancers, especially non-small cell lung cancer (NSCLC) and    squamous sarcoma;-   (8) diseases in which angiogenesis is associated with raised CXCR2    chemokine levels (e.g. NSCLC); and-   (9) cystic fibrosis, stroke, re-perfusion injury in the heart,    brain, peripheral limbs and sepsis.

Thus, the present invention provides a compound of formula (I), (I′),(I″) or (I′″), or a pharmaceutically-acceptable salt or solvate thereof,as hereinbefore defined for use in therapy.

In a further aspect, the present invention provides the use of acompound of formula (I), (I′), (I″) or (I′″), or a pharmaceuticallyacceptable salt or solvate thereof, as hereinbefore defined in themanufacture of a medicament for use in therapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention also provides a method of treating an inflammatory diseasein a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), (I′), (I″) or (I′″), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

The invention still further provides a method of treating an airwaysdisease in a patient suffering from, or at risk of, said disease, whichcomprises administering to the patient a therapeutically effectiveamount of a compound of formula (I), (I′), (I″) or (I′″), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of formula (I), (I′), (I″) or (I′″) may be in the rangefrom 0.001 mg/kg to 30 mg/kg.

The compounds of formula (I), (I′), (I″) or (I′″) and pharmaceuticallyacceptable salts and solvates thereof may be used on their own but willgenerally be administered in the form of a pharmaceutical composition inwhich the formula (I), (I′), (I″) or (I′″) compound/salt/solvate (activeingredient) is in association with a pharmaceutically acceptableadjuvant, diluent or carrier. Depending on the mode of administration,the pharmaceutical composition will preferably comprise from 0.05 to 99%w (per cent by weight), more preferably from 0.05 to 80% w, still morepreferably from 0.10 to 70% w, and even more preferably from 0.10 to 50%w, of active ingredient, all percentages by weight being based on totalcomposition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), (I′), (I″) or (I′″), or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedefined, in association with a pharmaceutically acceptable adjuvant,diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), (I′), (I″) or (I′″), or a pharmaceuticallyacceptable salt or solvate thereof, as hereinbefore defined, with apharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe lung and/or airways or to the skin) in the form of solutions,suspensions, heptafluoroalkane aerosols and dry powder formulations; orsystemically, e.g. by oral administration in the form of tablets,capsules, syrups, powders or granules, or by parenteral administrationin the form of solutions or suspensions, or by subcutaneousadministration or by rectal administration in the form of suppositoriesor transdermally.

The invention will now be further explained by reference to thefollowing illustrative examples, in which ¹H NMR spectra were recordedon Varian Unity Inova 400. The central solvent peak of chloroform-d(δ_(H) 7.27 ppm) were used as internal standard. Low resolution massspectra and accurate mass determination were recorded on aHewlett-Packard 1100 LC-MS system equipped with APCI/ESI ionisationchambers. All solvents and commercial reagents were laboratory grade andused as received. The nomenclature used for the compounds was generatedwith ACD/IUPAC Name Pro.

EXAMPLE 1N-(2-{3-[3R,S-(4-Chloro-phenoxy)-pyrroldin-1-yl]-2R,S-hydroxy-propoxy}-phenyl)-acetamidehydrochloride (i) 3-Hydroxy-pyrrolidine-1-carboxylic acid tert-butylester

A solution of pyrrolidin-3-ol (16.25 g, 186.5 mmol) anddi-tert-butyl-dicarbonate (40.7 g, 186.5 mmol) in dry THF (50 ml) undernitrogen was stirred over night. Concentration at reduced pressure andpurification by flash chromatography on silica (EtOAc:heptane, 7:3) gave31.9 g (91%) of the subtitle compound.

¹H-NMR (400 MHz, DMSO-d6): δ 4.87 (d, 1H, J=3.4 Hz), 4.21 (bs, 1H),3.31-3.22 (m, 3H), 3.10 (d, 1H, J=11.5 Hz), 1.83 (m, 1H), 1.72 (m, 1H),1.39 (s, 9H).

APCI-MS: m/z 132 [MH⁺-56]

(ii) 3-(4-Chloro-phenoxy)-pyrrolidine

3-Hydroxy-pyrrolidine-1-carboxylic acid tert butyl ester (2.1 g, 9.9mmol) and triphenyl phosphine (2.59 g, 9.9 mmol) were dissolved in dryTHF (35 ml) under nitrogen. The solution was cooled to 0° C. and4-chlorophenol (1.28 g, 9.9 mmol) dissolved in dry THF (10 ml) was addedfollowed by diethyl azodicarboxylate (DEAD) (1.55 ml, 9.9 mmol). After15 minutes the ice bath was removed and the reaction was stirredovernight. The reaction mixture was concentrated under reduced pressureand the residue was stirred with ether. The solid triphenyl phosphineoxide was filtered off. The solution was washed three times with sodiumhydroxide (1M) and concentrated. The BOC-protected product was purifiedby flash chromatography on silica using EtOAc/heptane as eluant. It wasdissolved in dichloromethane (35 ml) and trifluoroacetic acid (17 ml).The reaction mixture was stirred at room temperature overnight,concentrated and purified by flash chromatography on silica(MeOH:CHCl₃:NH₃, 100:100:1) to give the subtitle compound (1.72 g, 88%).

¹H-NMR (400 MHz, DMSO-d6): δ 7.30 (d, 2H, J=8.9 Hz), 6.91 (d, 2H, J=8.9Hz), 4.82 (m, 1H), 3.03 (dd, 1H, J=12.3, 5.4 Hz), 2.82 (m, 3H), 1.99 (m,1H), 1.72 (m, 1H).

APCI-MS: m/z 198 [MH⁺]

(iii)N-(2-{3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy-propoxy}-phenyl)-acetamidehydrochloride

A solution of 3-(4-Chloro-phenoxy)-pyrrolidine (0.059 g, 0.298 mmol) andN-acetyl-2-(2,3-epoxypropoxy)aniline (0.062 g, 0.299 mmol) in EtOH (1.5ml, 99.5%) was stirred for 3 hours at 75° C. in a sealed vial. Thesolvent was evaporated after completion of the reaction and the residuewas purified on silica (CH₂Cl₂:MeOH, 98:2 to 97:3) to give 88 mg of thefree amine of the title compound. The amine was dissolved in MeOH:water1:1 (30 ml), and the solution was acidified with 2M hydrochloric acid.The methanol was evaporated and the residual water solution waslyophilized to give 92 mg (70%) of the title compound as a white solid.

APCI-MS: m/z 405.2, 407.2 [MH⁺, isotope pattern]

EXAMPLE 2N-(5-Chloro-2-{3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy-propoxy}-phenyl)-acetamtidehydrochloride (i) N-(5-Chloro-2-hydroxy-phenyl)-acetamide

A solution of 4-amino-2-chlorophenol (2.0 g; 13.9 mmol) and aceticanhydride (1.77 g, 17.3 mmol) in water (40 ml) was stirred vigorouslyfor 5 minutes. The reaction mixture was then heated with stirring to 60°C. for 30 minutes, and was then allowed to cool. A pink solid was formedand the precipitate was collected by filtration, washed twice withwater, and dried to give 1.8 g (70%) of the subtitle compound.

¹H-NMR (400 MHz, DMSO-d₆): δ 10.09 (1H, s); 9.25 (1H, bs); 7.93 (1H, s);6.93 (1H, dd, J 8.8, 2.7 Hz); 6.84 (1H, d, J 8.6 Hz); 2.09 (3H, s)

APCI-MS: m/z 186.0 [MH⁺]

(ii) N-(5-Chloro-2-oxiranylmethoxy-phenyl)-acetamide

A solution of N-(5-Chloro-2-hydroxy-phenyl)-acetamide (0.499 g, 2.68mmol), K₂CO₃ (0.60 g, 4.35 mmol) and epibromohydrin (0.405 g, 2.95 mmol)in DMF (5 ml) was heated with stirring at 50° C. for 2 hours. Themixture was then partitioned between EtOAc and water 40+40 ml. Theorganic phase was washed twice with water and once with brine andfinally concentrated in vacuo to give a crude product. The crude productwas purified on silica (heptane:EtOAc, 1:1), to give 0.43 g (66%) of awhite solid.

¹H-NMR (400 MHz, CDCl₃): δ 8.46 (1H, d, J 2.3 Hz); 7.90 (1H, bs); 6.98(1H, dd, J 8.7, 2.4 Hz); 6.83 (1H, d, J 8.8 Hz); 4.36 (1H, dd, J 11.5,2.4 Hz); 3.94 (1H, dd, J 11.6, 6.0 Hz); 3.41-3.36 (1H, m); 2.97 (1H, dd,J 4.7, 4.2 Hz); 2.80 (1H, dd, J 4.6, 2.6 Hz); 2.23 (3H, s)

(iii)N-(5-Chloro-2-{3-[3R,S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2R,S-hydroxy-propoxy}-phenyl)-acetamidehydrochloride

Prepared by a process analogous to that described in Example 1, step(iii).

EXAMPLE 3N-(2-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)-acetamide

Prepared according to the methods described in Example 1. Purified andisolated as the free amine in 73% yield by C₁₈-column chromatography(H₂O:CH₃CN, 0.1M NH₄OAc buffer, gradient 30% to 95% CH₃CN).

APCI-MS m/z: 453, 455 [MH⁺]

¹H NMR (400 MHz, CDCl₃): δ 7.32(d, 1H), 7.01(d, 1H), 6.85-8.80(m, 2H),6.78-6.69 (m, 3H), 4.31 (m, 1H), 4.15-4.09(m, 1H), 4.18-3.18(bs, 3H),2.91(m, 1H), 2.71(m, 1H), 2.62-2.52(m, 3H), 2.35(m, 1H), 2.05-1.93(m,2H), 1.89-1.77(m, 2H)

EXAMPLE 41-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanoldihydrochloride

N-(2-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide(1.418 g, 3.13 mmol) was dissolved in 50 ml HCl (35%/aq, puriss) andrefluxed overnight. The product precipitated and was filtered and driedto give 0.835 g (65%) of the title compound.

APCI-MS m/z: 411, 413 [MH⁺]

¹H NMR (400 MHz, CDCl₃): δ 8.39-3.31 (m, 2H), 7.31(d, 1H), 7.01-6.98(m,3H), 6.94-6.91(m, 1H), 6.75(dd, 1H), 4.31(m, 1H), 4.12-4.02 (m, 2H),3.92(dd, 1H), 2.90(m, 1H), 2.69(m, 1H), 2.62-2.51(m, 2H), 2.46(dd, 1H),2.34(m, 1H), 2.18(s, 3H), 2.04-1.93(m, 2H), 1.89-1.77(m, 2H).

EXAMPLE 5N-(2-{3-[3-(3,4-dichlorophenoxy)-1-pyrrolidinyl)-2-hydroxypropoxy}phenyl)-acetamidehydrochloride

Prepared according to the methods described in Example 1 to give 68 mg(68%) of the title compound as a white solid.

APCI-MS m/z: 439, 441 [MH⁺]

EXAMPLE 62-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoicacid methyl ester (i) 2-Oxiranylmethoxy-benzoic acid methyl ester

Prepared according to the method described in Example 2, step (ii).

¹H-NMR: (400 MHz, CDCl₃): δ 7.81 (1H, dd, J 7.7, 1.7 Hz); 7.46 (1H, dt,J 7.7, 1.7 Hz); 7.05-6.98 (2H, m); 4.33 (1H, dd, J 11.3, 3.0 Hz); 4.11(1H, dd, J 11.3. 4.8 Hz); 3.90 (3H, s); 3.43-3.37 (1H, m); 2.93-2.90(2H, m)

(ii)2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoicacid methyl ester

Prepared according to the method described in Example 1, step (ii).Isolated as the free amine

¹H-NMR: (400 MHz, CDCl₃): δ 7.81 (1H, dd, J 8.1, 1.8 Hz); 7.46 (1H, dt,J 7.8, 1.7 Hz); 7.03-6.91 (4H, m); 6.86-6.82 (2H, m); 4.28-4.10 (3H, m);4.08-4.00 (1H, m); 3.88 (3H, s); 2.92-2.84 (1H, m); 2.83-2.76 (1H, m);2.66-2.53 (2H, m); 2.46 (1H, t, J 10.2 Hz); 2.36 (1H, t, J 10.2 Hz);2.02-1.92 (2H, m); 1.86-1.74 (2H, m); 1.63 (1H, bs)

APCI-MS: m/z 404.2 [MH⁺]

EXAMPLE 72-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionicacid methyl ester (i) Methyl2-[(2-hydroxybenzoyl)amino]-2-methylpropanoate

To a solution of 2-(chlorocarbonyl)phenyl acetate (20 mmol, 3.96 g) intoluene (50 ml) were N-ethyl-N,N-diisopropylamine (22 mmol, 2.84 g) and2-methylalanine (22 mmol, 2.27 g) added. After stirring the reactionmixture at room temperature overnight, the mixture was diluted with 250ml toluene and was washed with 1.8% HCl/aq (250 ml) and sat. NaCl/aq(250 ml). The organic phase was dried over Na₂SO₄ and concentrated underreduced pressure. The residue was dissolved in MeOH (50 mL) and 3 dropsof conc. H₂SO₄ were added. The mixture was refluxed for 2 hours andconcentrated under reduced pressure. The residue was dissolved in 250 mLEtOAc and washed with sat. NaHCO₃/aq (250 ml) and sat. NaCl/aq (250 ml).The organic phase was dried over Na₂SO₄ and concentrated at reducedpressure. The resulting crude material was used without furtherpurification.

APCI-MS m/z: 238 [MH+]

(ii) Methyl 2-methyl-2-{[2-(2-oxiranylmethoxy)benzoyl]amino}propanoate

A solution of methyl 2-[(2-hydroxybenzoyl)amino]-2-methylpropanoate,K₂CO₃ (20 mmol, 2.68 g) and 2-(chloromethyl)oxirane (22 mmol, 2.03 g) inacetonitrile (60 ml) was stirred at reflux temperature overnight. Thereaction mixture was diluted with EtOAc and washed with 1.8% HCl/aq (250ml) and sat. NaCl/aq (250 ml). The organic phase was dried over Na₂SO₄and concentrated at reduced pressure. The residue was purified onC₁₈-column (H₂O:CH₃CN, 0.1M NH₄OAc buffer, gradient 10% to 95% CH₃CN) togive the subtitle compound (244 mg, 5% yield, two steps).

APCI-MS m/z: 294 [MH+]

¹H NMR (400 MHz, CDCl₃): δ 8.40(s, 1H), 8.14 (dd, 1H), 7.41 (dt, 1H),7.07 (t, 1H), 6.90 (d, 1H), 4.44 (dd, 1H), 4.07 (dd, 1H), 3.74 (s, 3H),3.45 (m, 1H), 2.94 (dd, 1H), 2.84 (dd, 1H), 1.64 (d, 6H)

(iii)2-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionicacid methyl ester

A toluene solution of 4-(3,4-difluorophenoxy)piperidine (0.03 ml, 0.5 M)was mixed with a toluene solution of methyl2-methyl-2-{[2-(2-oxiranylmethoxy)benzoyl]amino}-propanoate (0.03 ml,0.5 M). The mixture was diluted with 0.20 ml toluene and 0.05 mlmethanol. The reaction mixture was stirred overnight at 100° C. insealed vials. The product were concentrated in vacuo and used withoutany purification.

APCI-MS m/z: 507 [MH+]

¹H NMR (400 MHz, CDCl₃) δ 8.13(s, 1H), 7.90 (dd, 1H), 7.33 (dt, 1H),7.07-6.96 (m, 2H), 6.89 (d, 1H), 6.73-6.68 (m, 1H), 6.58-6.55 (m, 1H),4.77-4.72 (m, 1H), 4.49 (bs, 1H), 4.20-4.13 (m, 2H), 3.69 (s, 3H),3.58-3.44 (m, 2H), 3.39-3.26 (m, 4H), 2.54-2.40 (m, 2H), 2.13-2.04 (m,2H), 1.60 (d, 6H)

EXAMPLE 8N-[2-({(1R,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopentyl}oxy)phenyl]acetamideandN-[2-({(1S,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopentyl}oxy)phenyl]acetamide(i) N-[2-(2-cyclopenten-1-yloxy)phenyl]acetamide

To a suspension of sodium hydride (60 proc. in paraffin; 297 mg, 7.43mmol, 1.1 equiv.) in DMF (3 ml) a solution of 2-acetamido-phenol (1.02g, 6.75 mmol, 1.0 equiv.) in DMF (12 ml) was added dropwise at 0° C.After 30 minutes chlorocyclopent-2-ene (R. Moffett, Organzic Synthesis,Wiley: New York 1963, Collect. Vol. IV, p.238-241) (762 mg, 0.76 ml,7.43 mmol, 1.1 equiv.) was added by a syringe and stirring was continuedovernight. Aqueous work-up followed by flash chromatography on silicagel (heptane/ethyl acetate, 2:1 continued to 1:1) afforded 992 mg (68%)of the subtitle compound as a dark, yellow oil.

¹H-NMR (400 MHz, CDCl₃): δ 8.35 (1H, d, J 8.0 Hz), 7.73 (1H, bs), 7.00(1H, td, J 7.9, 1.5 Hz), 6.90-6.95 (2H, m), 6.17 (1H, m), 5.95 (1H, m),5.36 (1H, d, J 5.9 Hz), 2.59 (1H, m), 2.38 (2H, m), 2.17 (3H, s), 1.97(1H, m).

MS-ESI+: m/z 218.1 [MH+].

(ii) N-{2-(6-oxabicyclo[3.1.0]hex-2-yloxy)phenyl}acetamide

To an ice bath cooled solution ofN-[2-(2-cyclopenten-1-yloxy)phenyl]acetamide (149 mg, 686 μmol, 1.0equiv.) in dichloromethane (4 ml) m-chloroperbenzoic acid (85 proc.; 146μmol, 1.1 equiv.) was added. After stirring overnight with slowlywarming up to an ambient temperature the reaction mixture was diluted bytertbutyl(methyl)ether, washed successively by a sat. sodium bisulfatesolution, 5 proc. sodium hydroxide and brine and dried over sodiumsulfate. Evaporation of the solvent and flash chromatography on silicagel (ethyl acetate/heptane, 2:3 continued to ethyl acetate) yielded 93mg (58%) of the subtitle compound as a mixture of the trans, (minor) andthe cis (major) diastereoisomeric epoxides as a pale yellow oil. Thecis/trans ratio was determined as 2:1 by ¹H-NMR.

¹H-NMR (400 MHz, CDCl₃): δ 8.39 (1H, [A], m), 8.34 (1H, [B], d, J 8.2Hz), 7.91(1H, [A], bs), 7.59 (1H, [B], bs), 6.92-7.25 (3H, [A]+3H [B],m), 4.89 (1H, [B], d, J 5.2 Hz), 4.77 (1H, [A], td, J 8.0, 1.3 Hz), 3.66(1H, [B], m), 3.64 (1H, [B], m), 3.60 (1H, [A], m), 3.54 (1H, [A], m),2.23 (1H, [B], d, J 8.4 Hz), 2.21 (3H, [A], s), 2.19 (3H, [B], s), 2.10(2H, [A], m), 1.72-1.92 (m), 1.53-1.63 (m), (2H, [A]+3H, [B]). (A=trans,B=cis)

MS-ESI+: m/z 234.1 [MH+].

(iii)N-[2-({(1R,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopentyl}oxy)phenyl]acetamideandN-[2-({(1S,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopentyl}oxy)phenyl]acetamide

N-{2-(6-oxabicyclo[3.1.0]hex-2-yloxy)phenyl}acetamide (racemic mixtureof the trans and cis diastereoisomers) (87 mg, 373 μmol, 1.0 equiv.) and4-(3,4-dichlorophenoxy)piperidine (92 mg, 394 μmol, 1.06 equiv.) weredissolved in 2 M lithium perchlorate in acetonitrile (3 ml) and heatedin a sealed tube over night at 85° C. Aqueous work-up and flashchromatography of the crude on silica gel (heptane/ethylacetate/methanol/ammonia=1:3:0:0 continued to 0:90:10:1 to 0:80:20:3)led to the separation of two diastereoisomeric addition products to give24 mg (14%) of the (1S,2S,3R) diastereoisomer (first eluted) and 75 mg(42%) of the second eluted (1R,2S,3R) diastereoisomer.

For (1S,2S,3R) diastereoisomer:

¹H-NMR (400 MHz, CDCl₃): δ 8.27 (1H, dd, J 7.6, 1.7 Hz), 7.91 (1H, s),7.29 (1H, d, J 8.9 Hz), 6.88-7.00 (4H, m), 6.73 (1H, dd, J 8.9, 2.8 Hz),4.45 (1H, m), 4.28 (1H, hept, J 3.6 Hz), 4.18 (1H, dd, J 7.1, 4.6 Hz),2.87 (3H, m), 2.71 (1H, q, J 7.5 Hz), 2.15 (3H, s), 2.11 (1H, m),1.78-2.02 (7H, m).

MS-APCI+: m/z 479.1 [MH+].

For (1R,2S,3R) diastereoisomer:

¹H-NMR (400 MHz, CDCl₃): δ 8.20-8.25 (2H, m), 7.29 (1H, d, J 8.9 Hz),6.91-7.00 (4H, m), 6.74 (1H, dd, J 8.9, 2.8 Hz), 4.46 (1H, bq, J 4.8Hz), 4.29 (1H, m), 4.13 (1H, d, J 7.2 Hz), 2.95 (2H, m), 2.84 (2H, m),2.50 (2H, m), 2.15 (3H, s), 1.93-2.07 (5H, m), 1.82 (2H, m), 1.58 (1H,m).

MS-APCI+: m/z 479.1 [MH+].

EXAMPLE 9N-[2-({(2,3-trans)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclohexyl}oxy)phenyl]acetamide(i) N-[2-(2-cyclohexen-1-yloxy)phenyl]acetamide

2-Cyclohexenol (491 mg, 0.49 ml, 5.00 mmol, 1.0 equiv.),2-acetamidophenol (756 mg, 5.00 mmol, 1.0 equiv.) and triphenylphosphine(1.44 g, 5.50 mmol, 1.1 equiv.) were dissolved in THF (10 ml) and keptat ambient temperature by a water bath. After dropwise addition ofdiethyl azodicarbonic acid (871 mg, 0.78 ml, 5.00 mmol, 1.0 equiv.),dissolved in THF (3 ml), the reaction mixture was stirred over night.Extractive work-up and flash chromatography on silica gel(heptane/tertbutyl(methyl)ether=1:1) afforded 224 mg (19%) the titlecompound as a yellow oil.

MS-ESI+: m/z 232.2 [MH+].

(ii) N-[2-(7-oxabicyclo[4.1.0]hept-2-yloxy)phenyl]acetamide

To a solution of N-[2-(2-cyclohexen-1-yloxy)phenyl]acetamide (76 mg, 329μmol, 1.0 equiv.) in dichloromethane (5 ml) m-chlorobenzoic acid (85proz.; 121 mg, 559 μmol, 1.7 equiv.) was added at 0° C. Stirring wascontinued overnight while the reaction mixture was allowed to warm upslowly to room temperature. The heterogenous mixture was diluted withethyl acetate and washed with sat. sodium sulfite, 5% sodium hydroxideand brine. Drying over sodium sulfate, evaporation of the solvent andflash chromatography on silica gel provided 59 mg (73%) of the titlecompound as a mixture of the diastereoisomers (ratio A:B=trans:cis=5:3[¹H-NMR]).

¹H-NMR (400 MHz, CDCl₃): δ 8.35 (1H, [A]+1H, [B], m), 8.02 (1H, [A],bs), 7.70 (1H, [B], bs), 6.95-7.04 (3H, [A]+3H, [B], m), 4.62 (1H, [A],dd, J 8.4, 5.5, 2.1 Hz), 4.55 (1H, [B], dd, J 7.5, 6.7 Hz), 3.30-3.36(2H, [A]+1H, [B], m), 3.19 (1H, [B], t, J 3.6 Hz), 1.26-2.23 (10H,[A]+10H, [B], m).

LC/MS-ESI+: m/z 248.1 [MH+(A)], 248.2 [MH+(B)].

(iii)N-[2-({(2,3-trans)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclohexyl}oxy)phenyl]acetamide

The diastereoisomeric mixture ofN-[2-(7-oxabicyclo[4.1.0]hept-2-yloxy)phenyl]acetamide (59 mg, 239 μmol,1.0 equiv.) and 4-(3,4-dichlorophenoxy)piperidine (56 mg, 239 μmol, 1.0equiv.) were dissolved in 2 M lithium perchlorate in acetonitrile (2 ml)and heated in a sealed tube over night at 85° C. Aqueous work-up andflash chromatography on silica gel (heptane/ethylacetate/methanol=50:100:3) gave 86 mg (75%) as a yellow oil in adiastereoisomeric ratio of 69:31=A:B (¹H-NMR). No separation of thediastereoisomers on reversed phase columns could be observed. Therelative stereochemistry of the major and minor diastereoisomers,respectively, could not be assigned due to the complex spectrum of themixture.

¹H-NMR (400 MHz, CDCl₃): δ 9.48 (1H, [A], bs), 9.25 (1H, [B], bs), 8.46(1H, [A]+1H, [B], t, J 9.1 Hz), 7.22-7.32 (2H, [A]+1H, [B], m),6.93-7.08 (4H, [A]+5H, [B], m), 6.72-6.76 (1H, [A]+1H, [B], m),4.08-4.30 (3H, [A]+3H, [B], m), 3.55-3.64 (2H, [A]+1H, [B], m),2.96-3.07 (2H, [A]+2H, [B], m), 2.71 (2H, [A]+3H, [B], m), 2.19 (3H,[A], s), 2.16 (3H, [B], s), 1.47-2.37 (10H, [A]+10H, [B], m).

MS-ESI+: m/z 493.1 [MH+(A, B)].

The following compounds were prepared by routes analogous to thosedescribed in the previous Examples.

EXAMPLE 10N-(5-Chloro-2-{3-[3-(3,4-dichloro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 473.1 475.1 [MH⁺]

EXAMPLE 11N-(3-Acetyl-2-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 495.1 497.1 [MH⁺]

EXAMPLE 12N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide

APCI-MS: m/z 453.1 455.1 [MH⁺]

EXAMPLE 13N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-fluoro-phenyl)-acetamide

APCI-MS: m/z 457.1 459.1 [MH⁺]

EXAMPLE 141-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol

APCI-MS: m/z 421.1 423.1 [MH⁺]

EXAMPLE 151-(7-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone

APCI-MS: m/z 463.1 465.1 [MH⁺]

EXAMPLE 16N-(4-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide

APCI-MS: m/z 515.1 517.1 [MH⁺]

EXAMPLE 17N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl)-acetamide

APCI-MS: m/z 457.1 459.1 [MH⁺]

EXAMPLE 18N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 453.1 455.1 [MH⁺]

EXAMPLE 19N-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 439.1 441.1 [MH⁺]

EXAMPLE 20N-(5-Chloro-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 439.1 441.1 [MH⁺]

EXAMPLE 21N-(3-Acetyl-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 461.1 [MH⁺]

EXAMPLE 22N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide

APCI-MS: m/z 419.1 [MH⁺]

EXAMPLE 23N-(2-{3-[3-(4-Chlorophenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-fluoro-phenyl)-acetamide

APCI-MS: m/z 423.1 [MH⁺]

EXAMPLE 241-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol

APCI-MS: m/z 387.1 [MH⁺]

EXAMPLE 251-(7-(3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone

APCI-MS: m/z 429.1 [MH⁺]

EXAMPLE 26N-(4-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide

APCI-MS: m/z 481.1 [MH⁺]

EXAMPLE 27N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl)-acetamide

APCI-MS: m/z 423.1 [MH⁺]

EXAMPLE 28N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 419.1 [MH⁺]

EXAMPLE 29N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 405.1 [MH⁺]

EXAMPLE 30N-(5-Chloro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 423.1 [MH⁺]

EXAMPLE 31N-(3-Acetyl-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 445.3 [MH⁺]

EXAMPLE 32N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide

APCI-MS: m/z 403.3 [MH⁺]

EXAMPLE 33N-(5-Fluoro-2-{3-[3-(4-fluoro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 407.1 [MH⁺]

EXAMPLE 341-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol

APCI-MS: m/z 371.1 [MH⁺]

EXAMPLE 351-(7-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone

APCI-MS: m/z 413.1 [MH⁺]

EXAMPLE 36N-(4-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide

APCI-MS: m/z 465.3 [MH⁺]

EXAMPLE 37N-(4-Fluoro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 407.1 [MH⁺]

EXAMPLE 38N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 403.1 [MH⁺]

EXAMPLE 39N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 389.1 [MH⁺]

EXAMPLE 40N-(5-Chloro-2-{3-[3-(3,4-difluoro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 441.1 [MH⁺]

EXAMPLE 41N-(3-Acetyl-2-{3-[3-(3,4-difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 463.3 [MH⁺]

EXAMPLE 42N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide

APCI-MS: m/z 421.1 [MH⁺]

EXAMPLE 43N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-fluoro-phenyl)-acetamide

APCI-MS: m/z 425.1 [MH⁺]

EXAMPLE 441-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol

APCI-MS: m/z 389.1 [MH⁺]

EXAMPLE 451-(7-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone

APCI-MS: m/z 431.1 [MH⁺]

EXAMPLE 46N-(4-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide

APCI-MS: m/z 483.3 [MH⁺]

EXAMPLE 47N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl)-acetamide

APCI-MS: m/z 425.1 [MH⁺]

EXAMPLE 48N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 421.1 [MH⁺]

EXAMPLE 49N-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 407.1 [MH⁺]

EXAMPLE 50N-(5-Chloro-2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 487.1 489.1 [MH⁺]

EXAMPLE 51N-(3-Acetyl-2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 509.1 511.1 [MH⁺]

EXAMPLE 52N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide

APCI-MS: m/z 467.1 469.1 [MH⁺]

EXAMPLE 53N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-fluoro-phenyl)-acetamide

APCI-MS: m/z 471.1 473.1 [MH⁺]

COMPARISON EXAMPLE 541-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol

APCI-MS: m/z 435.1 437.1 [MH⁺]

EXAMPLE 551-(7-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone

APCI-MS: m/z 477.1 479.1 [MH⁺]

EXAMPLE 56N-(4-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide

APCI-MS: m/z 429.1 431.1 [MH⁺]

EXAMPLE 57N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl)-acetamide

APCI-MS: m/z 471.1 473.1 [MH⁺]

EXAMPLE 58N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 467.1 469.1 [MH⁺]

EXAMPLE 59N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 453.1 455.1 [MH⁺]

EXAMPLE 60N-(5-Chloro-2-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 453.1 455.1 [MH⁺]

EXAMPLE 61N-(3-Acetyl-2-{3-[4-(4-chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 475.3 [MH⁺]

EXAMPLE 62N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-acetamide

APCI-MS: m/z 433.1 [MH⁺]

EXAMPLE 63N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-fluoro-phenyl)-acetamide

APCI-MS: m/z 437.1 [MH⁺]

COMPARISON EXAMPLE 641-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol

APCI-MS: m/z 401.1 [MH⁺]

EXAMPLE 651-(7-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone

APCI-MS: m/z 443.1 [MH⁺]

EXAMPLE 66N-(4-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-biphenyl-3-yl)-acetamide

APCI-MS: m/z 495.3 [MH⁺]

EXAMPLE 67N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-4-fluoro-phenyl)-acetamide

APCI-MS: m/z 437.1 [MH⁺]

EXAMPLE 68N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-methyl-phenyl)-acetamide

APCI-MS: m/z 433.1 [MH⁺]

EXAMPLE 69N-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl)-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 419.1 [MH⁺]

EXAMPLE 70N-{5-Chloro-2-[3-(8-chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide

APCI-MS: m/z 448.1 450.1 [MH⁺]

EXAMPLE 71N-{3-Acetyl-2-[3-(8-chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5-methyl-phenyl}-acetamide

APCI-MS: m/z 470.1 [MH⁺]

EXAMPLE 72N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4-methyl-phenyl}-acetamide

APCI-MS: m/z 428.1 [MH⁺]

EXAMPLE 73N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5-fluoro-phenyl}-acetamide

APCI-MS: m/z 432.1 [MH⁺]

EXAMPLE 741-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-3-(1H-indol-7-yloxy)-propan-2-ol

APCI-MS: m/z 396.1 [MH⁺]

EXAMPLE 751-{7-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-indol-1-yl}-ethanone

APCI-MS: m/z 438.1 [MH⁺]

EXAMPLE 76N-{4-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-biphenyl-3-yl}-acetamide

APCI-MS: m/z 490.1 [MH⁺]

EXAMPLE 77N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4-fluoro-phenyl}-acetamide

APCI-MS: m/z 432.1 [MH⁺]

EXAMPLE 78N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5-methyl-phenyl}-acetamide

APCI-MS: m/z 428.1 [MH⁺]

EXAMPLE 79N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide

APCI-MS: m/z 414.1 [MH⁺]

EXAMPLE 80N-{5-Chloro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide

APCI-MS: m/z 432.1 [MH⁺]

EXAMPLE 81N-{3-Acetyl-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5-methyl-phenyl}-acetamide

APCI-MS: m/z 454.3 [MH⁺]

EXAMPLE 82N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4-methyl-phenyl}-acetamide

APCI-MS: m/z 412.1 [MH⁺]

EXAMPLE 83N-{5-Fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide

APCI-MS: m/z 416.1 [MH⁺]

EXAMPLE 841-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-3-(1H-indol-7-yloxy)-propan-2-ol

APCI-MS: m/z 380.1 [MH⁺]

EXAMPLE 851-{7-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-indol-1-yl}-ethanone

APCI-MS: m/z 422.1 [MH⁺]

EXAMPLE 86N-{4-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-biphenyl-3-yl}-acetamide

APCI-MS: m/z 474.3 [MH⁺]

EXAMPLE 87N-{4-Fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide

APCI-MS: m/z 416.1 [MH⁺]

EXAMPLE 88N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-5-methyl-phenyl}-acetamide

APCI-MS: m/z 412.1 [MH⁺]

EXAMPLE 89N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-phenyl}-acetamide

APCI-MS: m/z 398.1 [MH⁺]

EXAMPLE 90N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS m/z: 453, 455 [MH+]

EXAMPLE 913-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 482, 484 [MH+]

EXAMPLE 921-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(2,6-dimethoxy-phenoxy)-propan-2-ol

APCI-MS m/z: 456, 458 [MH+]

EXAMPLE 931-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol

APCI-MS m/z: 426, 428 [MH+]

EXAMPLE 942-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 467, 469 [MH+]

EXAMPLE 951-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one

APCI-MS m/z: 452, 454 [MH+]

EXAMPLE 961-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone

APCI-MS m/z: 438, 440 [MH+]

EXAMPLE 973-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 418 [MH+]

EXAMPLE 981-(2,6-Dimethoxy-phenoxy)-3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-propan-2-ol

APCI-MS m/z: 392 [MH+]

EXAMPLE 991-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol

APCI-MS m/z: 362 [MH+]

EXAMPLE 100(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-aceticacid methyl ester

APCI-MS m/z: 447 [MH+]

EXAMPLE 101(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-aceticacid methyl ester

APCI-MS m/z: 491 [MH+]

EXAMPLE 1022-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionicacid methyl ester

APCI-MS m/z: 475 [MH+]

EXAMPLE 1032-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 403 [MH+]

EXAMPLE 1041-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone

APCI-MS m/z: 404 [MH+]

EXAMPLE 1051-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one

APCI-MS m/z: 388 [MH+]

EXAMPLE 1061-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone

APCI-MS m/z: 374 [MH+]

EXAMPLE 107N-[2-(3-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4-methylphenyl]acetamide

APCI-MS: m/z 480 [MH⁺]

EXAMPLE 1083-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 436 [MH+]

EXAMPLE 1091-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol

APCI-MS m/z: 380 [MH+]

EXAMPLE 110(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-aceticacid methyl ester

APCI-MS m/z: 465 [MH+]

EXAMPLE 1112-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 421 [MH+]

EXAMPLE 1121-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone

APCI-MS m/z: 422 [MH+]

EXAMPLE 1131-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one

APCI-MS m/z: 406 [MH+]

EXAMPLE 1141-(2-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone

APCI-MS m/z: 392 [MH+]

EXAMPLE 115N-(2-{3-[4-(3,4-dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 452.1 [MH⁺]

EXAMPLE 1163-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 434 [MH+]

EXAMPLE 1171-[3-(4-Chloro-phenoxy)-pyrroldin-1-yl]-3-(2,6-dimethoxy-phenoxy)-propan-2-ol

APCI-MS m/z: 408 [MH+]

EXAMPLE 1181-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol

APCI-MS m/z: 378 [MH+]

EXAMPLE 119(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-aceticacid methyl ester

APCI-MS m/z: 463 [MH+]

EXAMPLE 1202-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionicacid methyl ester

APCI-MS m/z: 491 [MH+]

EXAMPLE 1212-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 419 [MH+]

EXAMPLE 1221-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone

APCI-MS m/z: 420 [MH+]

EXAMPLE 1231-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one

APCI-MS m/z: 404 [MH+]

EXAMPLE 1241-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone

APCI-MS m/z: 390 [MH+]

EXAMPLE 125N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS m/z: 396 [MH+]

EXAMPLE 1263-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 425 [MH+]

EXAMPLE 127(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-aceticacid methyl ester

APCI-MS m/z: 454 [MH+]

EXAMPLE 1282-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 410 [MH+]

EXAMPLE 1294-{1-[2-Hydroxy-3-(2-propionyl-phenoxy)-propyl]-pyrrolidin-3-yloxy}-benzonitrile

APCI-MS m/z: 395 [MH+]

EXAMPLE 130N-(2-{2-Hydroxy-3-[3-(4-methoxy-phenoxy)-pyrrolidin-1-yl]-propoxy}-phenyl)-acetamide

APCI-MS m/z: 401 [MH+]

EXAMPLE 131N-(4-chloro-2-{3-[4-(3,4-dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 486[MH⁺]

EXAMPLE 1323-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 468, 470 [MH+]

EXAMPLE 1331-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol

APCI-MS m/z: 412, 414 [MH+]

EXAMPLE 134(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-aceticacid methyl ester

APCI-MS m/z: 497, 499 [MH+]

EXAMPLE 1352-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionicacid methyl ester

APCI-MS m/z: 525, 527 [MH+]

EXAMPLE 1362-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 453, 455 [MH+]

EXAMPLE 1371-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone

APCI-MS m/z: 454, 456 [MH+]

EXAMPLE 1381-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one

APCI-MS m/z: 438, 440 [MH+]

EXAMPLE 1391-(2-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone

APCI-MS m/z: 424, 426 [MH+]

EXAMPLE 140N-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS m/z: 421 [MH+]

EXAMPLE 1413-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 450 [NH+]

EXAMPLE 1422-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 435 [MH+]

EXAMPLE 1431-(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one

APCI-MS m/z: 420 [MH+]

EXAMPLE 144(2-{3-[4-(3,4-Difluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-aceticacid methyl ester

APCI-MS m/z: 479 [MH+]

EXAMPLE 145N-(2-{3-[3-(3,4-Difluoro-phenoxymethyl)-piperidin1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS m/z: 435 [MH+]

EXAMPLE 146N-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS m/z: 403 [MH+]

EXAMPLE 1473-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 432 [MH+]

EXAMPLE 1481-(2,6-Dimethoxy-phenoxy)-3-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-propan-2-ol

APCI-MS m/z: 406 [MH+]

EXAMPLE 1491-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol

APCI-MS m/z: 376 [MH+]

EXAMPLE 1501-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone

APCI-MS m/z: 388 [MH+]

EXAMPLE 1512-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 417 [MH+]

EXAMPLE 1521-(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one

APCI-MS m/z: 402 [MH+]

EXAMPLE 153(2-{3-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-aceticacid methyl ester

APCI-MS m/z: 461 [MH+]

EXAMPLE 154N-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS m/z: 417 [MH+]

EXAMPLE 1553-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 446 [MH+]

EXAMPLE 1561-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol

APCI-MS m/z: 390 [MH+]

EXAMPLE 1571-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone

APCI-MS m/z: 402 [MH+]

EXAMPLE 1582-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionicacid methyl ester

APCI-MS m/z: 503 [MH+]

EXAMPLE 1592-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 431 [MH+]

EXAMPLE 1601-(2-{3-[3-(4-Fluoro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone

APCI-MS m/z: 432 [MH+]

EXAMPLE 161N-(2-{3-[4-(4-Acetylamino-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS m/z: 442 [MH+]

EXAMPLE 162N-(4-{1-[3-(2-Acetyl-phenoxy)-2-hydroxy-propyl]-piperidin4-yloxy}-phenyl)-acetamide

APCI-MS m/z: 427 [MH+]

EXAMPLE 163N-(4-cyano-2-{3-[4-(3,4-dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 477 [MH⁺]

EXAMPLE 1643-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 448 [MH+]

EXAMPLE 1651-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-3-(2-methoxy-phenoxy)-propan-2-ol

APCI-MS m/z: 392 [MH+]

EXAMPLE 1661-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone

APCI-MS m/z: 404 [MH+]

EXAMPLE 1672-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-2-methyl-propionicacid methyl ester

APCI-MS m/z: 505 [MH+]

EXAMPLE 1682-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 433 [MH+]

EXAMPLE 1691-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-6-methoxy-phenyl)-ethanone

APCI-MS m/z: 434 [MH+]

EXAMPLE 1701-(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one

APCI-MS m/z: 418 [MH+]

EXAMPLE 171(2-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-benzoylamino)-aceticacid methyl ester

APCI-MS m/z: 477 [MH+]

EXAMPLE 172N-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS m/z: 433 [MH+]

EXAMPLE 1733-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionicacid methyl ester

APCI-MS m/z: 462 [MH+]

EXAMPLE 1741-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-ethanone

APCI-MS m/z: 418 [MH+]

EXAMPLE 1752-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-N,N-dimethyl-benzamide

APCI-MS m/z: 447 [MH+]

EXAMPLE 1761-(2-{3-[3-(4-Chloro-phenoxymethyl)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propan-1-one

APCI-MS m/z: 432 [MH+]

EXAMPLE 177N-[2-({(1R,2R)-2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-1-hydroxycyclopentyl}methoxy)phenyl]acetamideEXAMPLE 178 Methyl(2S,4R)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-[(4-chlorobenzyl)oxy]-2-pyrrolidinecarboxylatehydrochloride EXAMPLES 179-189

Starting Materials:

A) (3,4-Dichloro-phenyl)-piperidin-4yl-amine

In a nitrogen filled reaction vessel 4-oxo-piperidine-1-carboxylic acidtert-butyl ester (2.46 g, 12.3 mmol) and 3,4-dichloro-phenylamine (1.0g, 6.17 mmol) were dissolved in dichloromethane (28 ml) and acetic acid(2.12 ml). Sodium triacetoxyborohydride (3.67 g, 17.3 mmol) was added atroom temperature. The reaction was stirred over night and then pouredinto a sodium hydrogencarbonate solution (5%). The water phase wasshaken three times with ethyl acetate (EtOAc). The combined organicphase was dried over sodium sulfate, evaporated and purified by flashchromatography (EtOAc:Heptane 3:7) giving 1.7 g, 81% of pure compound.The BOC-protected title compound was dissolved in dichloromethane (26ml) and trifluoro acetic acid (13 ml) and stirred at room temperaturefor 3 h, evaporated and dissolved in diethyl ether and sodium hydroxide(1 M). The organic layer was separated and the water phase washed twicewith ether. The combined organic layer was washed with a small portionof brine, dried over sodium sulfate and evaporated to give 1.15 g (76%)of the title compound.

¹H-NMR (400 MHz, DMSO-d6): δ 7.20 (d, 1H, J=8.9 Hz), 6.73 (d, 1H, J=2.7Hz), 6.54 (dd, 1H, J=8.8, 2.7 Hz), 5.95 (d, 1H, J=8.1 Hz), 3.22 (m, 1H,2.91 (bd, 2H, J=12.6 Hz), 2.51 (m, 2H), 2.02 (bs, 1H), 1.81 (bd, 2H,J=12.4 Hz), 1.18 (m).

APCI-MS: m/z 245 [M+]

B) (4-Chloro-phenyl)-piperidin-4yl-amine

Was synthesised in the same way as (A) from4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.59 g, 18.0 mmol),4-chloro-phenylamine (1.15 g, 9.0 mmol) and sodium triacetoxyborhydride(5.34 g, 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml).The deprotection was run in dichloromethane (37 ml) and trifluoro aceticacid (18 ml). Yield 1.5 g, 79%.

¹H-NMR (400 MHz, DMSO-d6): δ 7.04 (d, 2H, J=8.9 Hz), 6.55 (d, 2H, J=8.9Hz), 5.62 (d, 1H, J=8.1 Hz), 3.18 (m, 1H), 2.92 (bd, 2H, J=12.6 Hz),2.50 (m, 2H), 1.99 (bs, 1H), 1.82 (d, 2H, J=12.7 Hz), 1.18 (m, 2H).

APCI-MS: m/z 211 [MH+]

C) (4-Fluoro-phenyl)-piperidin-4yl-amine

Was synthesised in the same way as (A) from4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.59 g, 18.0 mmol),4-fluoro-phenylamine (1.0 g, 9.0 mmol) and sodium triacetoxyborhydride(5.34 g, 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml).The deprotection was run in dichloromethane (37 ml) and trifluoro aceticacid (18 ml). Yield 1.1 g, 63%.

¹H-NMR (400 MHz, DMSO-d6): δ 6.85 (t, 2H, J=9.0 Hz), 6.51 (dd, 2H,J=9.1, 4.6 Hz), 5.27 (d, 1H, J=8.2 Hz), 3.13 (m, 1H), 2.89 (bd, 2H,J=12.5 Hz), 2.48 (m, 2H), 1.80 (bd, 2H, J=12.3 Hz), 1.14 (m, 2H).

APCI-MS: m/z 195 [MH+]

D) (3,4-Difluoro-phenyl)-piperidin-4yl-amine

Was synthesised in the same way as (A) from4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.59 g, 18.0 mmol),3,4-difluoro-phenylamine (1.16 g, 9.0 mmol) and sodiumtriacetoxyborohydride (5.34 g, 25.2 mmol) in dichloromethane (40 ml) andacetic acid (3.1 ml). The deprotection was run in dichloromethane (37ml) and trifluoro acetic acid (18 ml). Yield 1.26 g, 66%.

¹H-NMR (400 MHz, DMSO-d6): δ 7.05 (dt, 1H, J=10.8, 9.2 Hz), 6.50 (ddd,1H, J=14.1, 7.0, 2.8 Hz), 6.32 (bd, 1H, J=9.20 Hz), 5.64 (d, 1H, J=8.14Hz), 3.17 (m, 1H), 2.90 (bd, 2H, J=12.6 Hz), 2.50 (m, 2H), 2.00 (bs,1H), 1.81 (bd, 2H, J=12.6 Hz), 1.16 (m, 2H)

APCI-MS: m/z 213 [MH+]

EXAMPLE 179N-(2-{3-[4-(3,4-Dichloroanilino)-1-piperinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide

APCI-MS: m/z 466[MH+]

EXAMPLE 180N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 418[MH+]

EXAMPLE 181N-(4-Chloro-2-{3-[4-(4-chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)-acetamide

APCI-MS: m/z 452[MH+]

EXAMPLE 182N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-cyanophenyl)acetamide

APCI-MS: m/z 443[MH+]

EXAMPLE 183N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide

APCI-MS: m/z 432[MH+]

EXAMPLE 184N-(5-Chloro-2-{3-[4-(4-fluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 436[MH+]

EXAMPLE 185N-(5-Chloro-2-{3-[4-(3,4-difluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 454[MH+]

EXAMPLE 186N-(5-Cyano-2-{3-[4-(4-fluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}-phenyl)acetamide

APCI-MS: m/z 427[MH+]

EXAMPLE 187N-(5-Cyano-2-{3-[4-(3,4-difluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 445[MH+]

EXAMPLE 188N-(2-{3-[4-(4-Fluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide

APCI-MS: m/z 416[MH+]

EXAMPLE 189N-(2-{3-[4-(3,4-Difluoroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide

APCI-MS: m/z 434[MH+]

EXAMPLE 190N-(2-{3-[3(S)-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-(R)-hydroxy-propoxy-phenyl)acetamidei) 3-(S)-(4-Chloro-phenoxy)-pyrrolidine CF₃COOH

To a solution of triphenyl phosphine (4.2 g, 16.02 mmol) in THF (75 mL)was added diethyl azodicarboxalate (2.52 mL) at 0° C., after 15 min4-chlorophenol (2.05 g, 16.02 mmol) was added and after another 10 min3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (3.0 g, 16.02mmol) in THF (20 mL) was added slowly. After addition was complete theice bath was removed and the reaction mixture was kept at roomtemperature overnight. The solvent was removed in vacuo and the residuewas stirred with diethyl ether, the solid triphenyl phosphine wasfiltered off. The residue was purified by flash chromatography (0-0.5%MeOH in CHCl₃) to give the subtitled compound (3.65 g, 76%) which wasdissolved in dichloromethane (60 mL) and trifluoroacetic acid (15 mL)was added. The reaction mixture was kept at room temperature for 30 min.The solvent was removed in vacuo. The residue was dissolved indichloromethane, diethylether and hexane were added. The solid wasfiltered off to give the subtitled compound 3.70 g, 97%.

¹H-NMR (CDCl₃, 400 MHz): δ 10.20 (s, 1H), 9.99 (s, 1H), 7.25 (d, J 8.8Hz, 2H), 6.78 (d, J 8.8 Hz, 2H), 4.99 (m, 1H), 3.41 (m, 4H), 2.30 (m1H), 2.20 (m, 1H).

APCI-MS: m/z 198 (MH⁺).

ii)N-(2-{3-[3(S)-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-(R)-hydroxy-propoxy-phenyl)acetamide

A mixture of 3-(S)-(4-chloro-phenoxy)-pyrrolidine.CF₃COOH (312 mg, 1.0mmol), N-acetyl-2-(2,3-epoxypropoxy)aniline (207 mg, 1.0 mmol), K₂CO₃(560 mg) in EtOH (10 mL) was stirred at 65° C. for 4 h. The solvent wasremoved in vacuo. The residue was partitioned between ethyl acetate andwater. The organic layer was washed with aqueous NHCl solution, thenwith water. The organic layer was dried over Na₂SO₄, filtered,concentrated. The residue was purified by flash chromatography (0-3%MeOH in CHCl₃) to give a mixture of diastereomers (310 mg, 77%). Thediastereomers were seperated by HPLC to giveN-(2-{3-[3(S)-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-(R)-hydroxy-propoxy-phenol)acetamide(57 mg)

¹H-NMR (CDCl₃, 400 MHz): δ 8.36 (m, 1H), 8.25 (s, 1H), 7.25 (m, 2H),6.99 (m, 2H), 6.93 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.08 (m, 2H),3.96 (m, 1H), 3.11 (dd, J 5.9, 10.5 Hz, 1H), 3.01 (m, 1H), 2.82 (m, 2H),2.59 (m, 1H), 2.51 (dd, J 3.2, 12.0 Hz, 1H), 2.29 (m, 1H), 2.19 (s, 3H),2.01 (m, 1H). APCI-MS: m/z 405 (MH⁺).

EXAMPLE 191N-(2-{3-[3S-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2S-hydroxy-propoxy}-phenyl)-acetamidehydrochloride

The reaction was performed analogously to Example 190.

¹H-NMR (CDCl₃, 400 MHz): δ 8.35 (m, 1H), 8.26 (s, 1H), 7.24 (m, 2H),6.99 (m, 2H), 6.92 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.12 (m, 2H),3.95 (m, 1H), 2.95 (m, 2H), 2.80 (m, 3H), 2.52 (dd, 3.4, 12.2 Hz, 1H),2.30 (m, 1H), 2.19 (s, 3H), 2.01 (m, 1H).

APCI-MS: m/z 405 (MH⁺).

EXAMPLE 192N-(2-{3-[3(R)-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-(S)-hydroxy-propoxy-phenyl)acetamide

The reaction was performed analogously to Example 190.

¹H-NMR (CDCl₃, 400 MHz): δ 8.36 (m, 1H), 8.25 (s, 1H), 7.25 (m, 2H),6.99 (m, 2H), 6.93 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.08 (m, 2H),3.96 (m, 1H), 3.11 (dd, J 5.9, 10.5 Hz, 1H), 3.01 (m, 1H), 2.82 (m, 2H),2.59 (m, 1H), 2.51 (dd, J 3.2, 12.0 Hz, 1H), 2.29 (m, 1H), 2.19 (s, 3H),2.01 (m, 1H).

APCI-MS: m/z 405 (MH⁺).

EXAMPLE 193N-[5-Chloro-2-({(2S)-3-[(3S)-3-(4-chloro-phenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide

The reaction was performed analogously to Example 190.

¹H-NMR (CDCl₃, 400 MHz): δ 8.45 (m, 1H), 8.36 (br. S, 1H), 7.23 (m, 2H),6.95 (m, 1H), 6.85 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.07 (m, 2H),3.91 (m, 1H), 2.95 (m, 2H), 2.80 (m, 3H), 2.49 (dd, J 3.2, 12.0 Hz, 1H),2.30 (m, 1H), 2.19 (s, 3H), 2.03 (m, 1H).

APCI-MS: m/z 439 (MH⁺).

EXAMPLE 194N-[5-Chloro-2-({(2R)-3-[(3R)-3-(4-chloro-phenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide

The reaction was performed analogous to Example 190.

¹H-NMR (CDCl₃, 400 MHz): δ 8.45 (m, 1H), 8.36 (br. S, 1H), 7.23 (m, 2H),6.95 (m, 1H), 6.85 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.07 (m, 2H),3.91 (m, 1H), 2.95 (m, 2H), 2.80 (m, 3H), 2.49 (dd, J 3.2, 12.0 Hz, 1H),2.30 (m, 1H), 2.19 (s, 3H), 2.03 (m, 1H).

APCI-MS: m/z 439 (MH⁺).

EXAMPLE 195N-[5-Chloro-2-({(2S)-3-[(3R)-3-(4-chloro-phenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide

The reaction was performed analogously to Example 190.

¹H-NMR (CDCl₃, 400 MHz): δ 8.45 (m, 1H), 8.34 (br. S, 1H), 7.22 (m, 2H),6.94 (m, 1H), 6.85 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.08 (m, 2H),3.90 (m, 1H), 3.11 (dd, J 5.9, 10.5 Hz, 1H), 3.02 (m, 1H), 2.81 (m, 2H),2.58 (m, 1H), 2.49 (dd, J 3.5, 12.1 Hz, 1H), 2.30 (m, 1H), 2.18 (s, 3H),2.01 (m, 1H).

APCI-MS: m/z 439 (MH⁺).

EXAMPLE 196N-[5-Chloro-2-({(2R)-3-[(3S)-3-(4-chloro-phenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide

The reaction was performed analogous to Example 190.

¹H-NMR (CDCl₃, 400 MHz): δ 8.45 (m, 1H), 8.34 (br. S, 1H), 7.22 (m, 2H),6.94 (m, 1H), 6.85 (m, 1H), 6.75 (m, 2H), 4.80 (m, 1H), 4.08 (m, 2H),3.90 (m, 1H), 3.11 (dd, J 5.9, 10.5 Hz, 1H), 3.02 (m, 1H), 2.81 (m, 2H),2.58 (m, 1H), 2.49 (dd, J 3.5, 12.1 Hz, 1H), 2.30 (m, 1H), 2.18 (s, 3H),2.01 (m, 1H).

APCI-MS: m/z 439 (MH⁺).

EXAMPLE 197N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4,5-difluoro-phenyl)-acetamidei) 4,5-Difluoro-2-nitro-phenol

In a flask was dissolved 3,4-Difluorophenol (3.10 g, 23.7 mmole) inacetic acid (15 ml). To the stirred solution was added dropwise asolution of fuming HNO₃ (1.25 g, 29.7 mmole) in acetic acid (6 ml). Thetemperature was kept under 50° C. during the entire addition. Aftercompleted addition, the mixture was stirred for another hour. Thereaction mixture was then poured onto ice-water, giving precipitation ofa yellowish solid. The solid was collected by filtration, and dried. Thesolid was purified on silica (Heptane:EtOAc 5:1), giving the sub-titlecompound (2.05 g, 50%) as a yellow oil, which crystallizes on standing.

¹H-NMR (400 MHz, CDCl₃) δ: 10.61 (1H, s); 8.00 (1H, dd, J 9.6, 8.2 Hz);7.00 (1H, dd, J 10.4, 6.8 Hz)

ii) N-(4,5-Difluoro-2-hydroxy-phenyl)-acetamide

In a flask was added the product obtained in i) (0.59 g, 3.37 mmole),and acetic acid (10 ml). The solution was heated with stirring to 90°C., and Tin (powder, 1.60 g, 13.5 mmole) was added. The flask was sealedand heated with stirring for another hour, and the hot solution wasfiltered through celite. The filter was then washed with another 10 mlof hot acetic acid. To the filtrate was added water (25 ml) and aceticanhydride (0.5 ml, 5.29 mmole), and the resulting mixture was heatedwith stirring at 60° C. for 20 minutes. The mixture was allowed to cool,and was partitioned between EtOAc and water. The organic phase wascollected and washed with water and brine. The organic phase wasevaporated to give the 0.63 g (100%) of the sub-title compound as asolid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 10.25 (1H, s); 9.31 (1H, bs); 7.88 (1H, dd,J 12.8, 7.9 Hz); 6.83 (1H, dd, J 12.1, 7.7 Hz); 2.08 (3H, s)

iii) N-(4,5-Difluoro-2-oxiranylmethoxy-phenyl)-acetamide

In a vial was added the compound obtained in ii) (0.4 g, 2.137 mmole),epibromohydrine (0.35 g, 2.55 mmole), K₂CO₃ (0.6 g, 4.4 mmole) and DMF(2 ml). The vial was sealed and heated with stirring (2 hours, 60° C.).The mixture was then partitioned between EtOAc and water, and theorganic phase was washed twice with water and once with brine, and wasfinally evaporated to give a brown solid. The crude epoxide was purifiedon silica, to give 0.27 g (52%) of the sub-title compound as a slightlypink solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.37 (1H, dd, J 12.2, 8.8 Hz); 7.85 (1H, bs);6.78 (1H, dd, J 11.2, 7.1 Hz); 4.34 (1H, dd, 11.5, 2.2 Hz); 3.90 (1H,dd, 11.6, 6.3 Hz); 3.40-3.36 (1H, m); 2.98 (1H, t, J 4.5 Hz); 2.81 (1H,dd, J 4.7, 6.3 Hz); 2.22 (3H, s)

iv)N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4,5-difluoro-phenyl)-acetamide

In a vial was added the compound obtained in iii) (0.059 g, 0.24 mmole),3-(4-chlorophenoxy)-pyrrolidine (0.048 g, 0.24 mmole) and ethanol (2 ml,99.5%). The vial was sealed and the content was heated with stirring to75° C. for 2 hours. The crude solution was evaporated and the obtainedoil purified on silica to the title compound which was lyophilized asthe hydrochloride. The title compound was obtained as a white solid(0.075 g, 65%). The compound was a mixture of four stereoisomers, whichhad an effect on the NMR-spectra.

¹H-NMR (400 MHz, DMSO-d₆) δ: 10.78-10.30 (1H, m); 9.30 (1H, s); 8.07(1H, dd, J 12.8, 9.3 Hz); 7.40-7.34 (2H, m); 7.23 (1H, dd, J 12.7, 7.5Hz); 7.05-6.99 (2H, m); 6.19 (1H, bs); 5.23-5.11 (1H, m); 4.35 (1H, bs);4.08-3.97 (1.5H, m), 3.96-3.90 (1H, m); 3.84-3.70 (1.5H, m); 3.63-3.23(4H, m); 2.66-2.00 (5H, m)

APCI-MS: mm/z 411.1 [MH+]

EXAMPLE 198N-{5-Chloro-2-[2-hydroxy-3-(3-phenoxy-pyrrolidin-1-yl)-propoxy]-phenyl}-acetamide

The compound was prepared analogously to Example 197.

¹H-NMR (400 MHz, DMSO-d₆) δ: 10.80-10.36 (1H, m); 9.26 (1H, s); 8.14(1H, s); 7.32 (2H, t, J 8.35 Hz); 7.11-6.95 (5H, m); 6.31-6.02 (1H, m);5.25-5.12 (1H, m) 4.37 (1H, bs); 4.10-3.97 (1.5H, m); 3.95-3.88 (1H, m)3.84-3.68 (1.5H, m); 3.64-3.26 (4H, m); 2.65-2.52 (0.5H, m); 2.35-2.02(4.5H, m)

APCI-MS: m/z 405.2 [MH+]

EXAMPLE 199N-(5-Chloro-2-{2-hydroxy-3-[3-(4-nitro-phenoxy)-pyrrolidin-1-yl]-propoxy}-phenyl)-acetamide

The compound was prepared analogously to Example 197.

¹H-NMR (400 MHz, DMSO-d₆) δ: 10.95-10.48 (1H, m); 9.26 (1H, s); 8.24(2H, d, J 9.6 Hz); 8.13 (1H, bs); 7.23-7.17 (2H, m); 7.12-7.02 (2H, m);6.20 (1H, bs); 5.43-5.30 (1H, m); 4.38 (1H, m); 4.18-4.06 (0.5H, m);4.05-3.97 (1H, m); 3.95-3.87 (1H, m); 3.86-3.72 (1.5H, m); 3.69-3.27(4H, m); 2.73-2.60 (0.5H, m); 2.46-2.08 (4.5H, m)

APCI-MS: m/z 450.1 [MH+]

EXAMPLE 200N-(5-Acetyl-2-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

The compound was prepared analogously to Example 197.

APCI-MS: m/z 481.2, 483.2 [MH+]

EXAMPLE 2014-Acetylamino-3-{3-[3-(3,4-dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoicacid methyl ester

The compound was prepared analogously to Example 197.

APCI-MS: m/z 497.1, 499.2 [MH+]

EXAMPLE 202N-(3-(3-{3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-naphthalen-2-yl)-acetamide

The compound was prepared analogously to Example 197.

APCI-MS: m/z 489.2, 491.2 [MH+]

EXAMPLE 203N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-5-cyano-phenyl)-acetamide

The title compound was prepared according to the method in Example 197.

APCI-MS: m/z 430.2 [MH+]

EXAMPLE 2044-Acetylamino-3-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-benzoicacid methyl ester

The compound was prepared analogously to Example 197.

APCI-MS: m/z 463.2 [MH+]

EXAMPLE 205N-(3-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-naphthalen-2-yl)-acetamide

The title compound was prepared according to the method in Example 197.

APCI-MS: m/z 455.2 [MH+]

EXAMPLE 206N-(5-Cyano-2-{3-[4-(3,4-dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

The title compound was prepared according to the method in Example 197.

APCI-MS: m/z 478.2 480.1 [MH+]

EXAMPLE 207N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-5-trifluoromethyl-phenyl)-acetamide

The title compound was prepared according to the method in Example 197.

APCI-MS: m/z 521.1 523.2 [MH+]

EXAMPLE 208N-(5-Chloro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamidetrifluoroacetate

The title compound was prepared according to the method in Example 197.

APCI-MS: m/z 423.1, 424.9 [MH⁺]

EXAMPLE 209N-(5-Acetyl-2-{3-[3-(4-chloro-phenoxy)-pyrrolid-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamidetrifluoroacetate i) N-(5-Acetyl-2-oxiranylmetoxy-fenyl)-acetamide

To a solution of 4-acetyl-2-nitrophenol (0.50 g, 2.76 mmol) in THF (20ml) was added 10% Pd/C (0.15 g). The resultant mixture was hydrogenatedwith H₂ at 1 atm for 5 hours and was then filtered through celite andevaporated to give 0.63 g of a red oil. Water (20 ml) and aceticanhydride (0.35 g, 3.44 mmol) was added and the mixture was stirredvigorously for 5 minutes. The reaction mixture was then heated withstirring to 60° C. for 30 minutes, and was then allowed to cool. A redsolid was formed and the precipitate was collected by filtration, washedwith water and dried to give 0.27 g (1.40 mmol) ofN-(5-Acetyl-2-hydroxy-phenyl)-acetamide. This was dissolved in DMF (5ml). K₂CO₃ (0.34 g, 2.45 mmol) and epibromohydrin (0.21 g, 1.54 mmol)was added and the resulting mixture was heated with stirring at 50° C.for 3 hours. The mixture was partitioned between EtOAc and water 40+40ml. The organic phase was washed twice with water and once with brineand finally concentrated in vacuo to give a red oil. The crude productwas purified on silica (Heptane/EtOAc, 1:2-1:4) to give 110 mg (16%) ofthe subtitle compound.

¹H-NMR (400MHz, CDCl₃): δ 9.03 (1H, d, J1.9 Hz), 7.81 (1H, bs), 7.74(1H, dd, J8.6, 2.3 Hz), 6.96 (1H, d, J8.6 Hz), 4.48 (1H, dd, J11.3, 2.4Hz) 4.00 (1H, dd, J11.4, 6.4 Hz), 3.45-3.40 (1H, m), 2.99 (1H, t, J4.4Hz), 2.79 (1H, dd, J4.7, 2.6 Hz), 2.59 (3H, s), 2.26 (3H, s).

ii)N-(5-Acetyl-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamidetrifluoroacetate

The title compound was prepared according to the method described inExample 197.

APCI-MS: m/z 447, 449 [MH⁺]

EXAMPLE 210N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-methanesulfonamidei) 1-(2-Aminophenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanoldihydrochloride

A mixture ofN-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide(0.95 g, 2.34 mmol) and concentrated hydrochloric acid (25 mL) washeated (100-105° C.) for 3 hours then allowed to stand at roomtemperature overnight. The mixture was concentrated at reduced pressureto a third of its volume basified with saturated sodium hydrogencarbonate. The resulting suspension was extracted twice with ethylacetate. The organic extracts were dried, the solvent was evaporated atreduced pressure to give a pale brown oil. This oil was dissolved in aminimum amount of methanol, diluted with ethyl ether and the productprecipitated by addition of HCl-saturated ethyl ether. The product wasfiltered to afford the subtitle product (0.93 g, 91.2%).

APCI-MS: m/z 363 [MH⁺] for the free base.

ii)N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-methanesulfonamide

Methanesulfonyl chloride (35 mg, 0.3 mmol) was added to cold (0 C.),stirred mixture of the above amine (110 mg, 0.25 mmol) and pyridine (0.4mL) in dry dichloromethane (10 mL). The mixture was then stirred at roomtemperature for 1.5 hour then concentrated. The residue was partitionedbetween ethyl acetate and water. The organic phase was concentrated andthe residue was purified by flash chromatography (silica gel,dichloromethane-methanol, 25:1) to afford the title compound (68 mg,61.8%) as a foam.

¹H-NMR (400 MHz, CDCl₃): δ 7.51 (dd, 1H, J=1.4 and 8.0 Hz), 7.22 (m,2H), 7.10 (m, 1H), 7.68 (m, 1H), 6.92 (d, 1H, J=9.0 Hz), 6.76 (m, 2H),5.78 (very bs, 1H), 4.80 (m, 1H), 4.20 (m, 1H), 4.08 (m, 1H), 3.98 (m,1H), 3.16 (m, 1H), 3.01 (m, 1H), 2.96 (s, 3H), 2.89 (m, 2H), 2.74 (m,M), 2.68 (dd, 1H, J=4.0 and 12.2 Hz), 2.3 (m, 1H), and 2.02 (m, 1H).

¹³C-NMR, 400 MHz, CDCl₃): δ 155.9, 149.4, 129.4, 126.9, 125.8, 125.77,125.75, 122.29, 122.26, 122.17, 115.5, 113.50, 76.52, 76.49, 72.15,72.09, 67.18, 67.08, 60.24, 60.07, 57.96, 57.94, 53.18, 52.98, 39.1,31.92, 31.90.

APCI-MS: m/z 441[MH⁺].

EXAMPLE 211N-(5-Chloro-2-[3-[3,4-dichlorophenoxy)-1-pyrrodinyl]-2-hydroxypropoxy]-phenyl)ureai) N-(5-Chloro-2-hydroxyphenyl)urea

A solution of potassium cyanate (6.14 g, 75.6 mmol) in water (50 mL) wasadded dropwise to a stirred suspension of 2-amino-4-chlorophenol (5.00g, 34.8 mmol) in a mixture of acetic acid (350 mL) and water (250 mL)and the resulting solution was stirred at room temperature for 3 hours.The reaction mixture was extracted three times with ethyl ether. Theether extracts were combined and concentrated to a thick oil. A 10%solution of sodium hydrogen carbonate (250 mL) was added to the aboveoil. The solid product was filtered and washed several times with waterand recrystallized (toluene containing a little methanol) to afford thesubtitle compound (3.27 g, 50.4%).

¹H-NMR (400 MHz, DMSO-d6): δ 10.1 (s, 1H), 8.07 (d, 1H, J=2.2 Hz), 8.04(s, 1H), 6.75-6.78 (m, 2H), 6.29 (bs, 2H).

¹³C-NMR: δ 156.0, 144.1, 130.0, 122.5, 120.2, 117.5, 115.2.

ii) N-[5-Chloro-2-(2-oxiranylmethoxy)phenyl]urea

A suspension of N-(5-chloro-2-hydroxyphenyl)urea (53 mg, 0.28 mmol),cesium carbonate (92 mg, 0.28 mmol) and epibromohydrine (49 mg, 0.36mmol) in dry DMF (0.6 mL) was stirred at room temperature for 24 hours.The mixture was then partitioned between ethyl acetate and water. Theorganic phase was washed with water three times, dried and concentratedto a solid residue. This crude product was recrystallized (ethyl etherand heptane to afford the subtitle compound (18 mg, 26.5%).

¹H-NMR (400 MHz, DMSO-d6): δ 8.20 (d, 1H, J=2.2 Hz), 8.00 (s, 1H), 7.00(d, 1H, J=8.8 Hz), 6.88 (dd, 1H, J=2.4 and 8.6 Hz), 6.40 (bs, 2H), 4.40(dd, 1H, J=2.2 and 12.0 Hz), 3.90 (dd, 1H, J=6.6 and 12.0 Hz), 3.37 (m,1H), 2.88 (t, 1H, H=4.8 Hz), 2.74 (m, 1H).

iii)N-(5-Chloro-2-[3-[3,4-dichlorophenoxy)-1-pyrrodinyl]-2-hydroxypropoxy]-phenyl)urea

A solution of the subtitle compound (ii) (16 mg, 0.07 mmol) and3-(3,4-dichlorophenoxy)pyrrolidine (17 mg, 0.07 mmol) in absoluteethanol (1 mL) for 2 hours. The solvent was removed under reducedpressure and the residue was purified by flash chromatography(dichloromethane-methanol, 15:1) to afford the title compound (11 mg,33%).

¹H-NMR (400 MHz, DMSO-d6): δ 8.18 (d, 1H, J=2.6 Hz), 7.94 (s, 1H), 7.5(d, 1H, J=0.0 Hz), 7.16 (d, 1H, J=2.1 Hz), 6.82-6.98 (m, 3H), 6.33 (bs,2H), 4.98 (m, 1H), 4.90 (m, 1H), 3.85-4.07 (m, 3H), 2.63-2.93 (m, 5H),2.21-2.30 (m, 1H), 1.74 (m, 1H).

APCI-MS: m/z 198 [MH⁺]

EXAMPLE 2121-(3-{2-[((Aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(4-chlorophenoxy)pyrrolidinium2,2,2-trifluoroacetate i) N-(2-Hydroxyphenyl)urea

A solution of potassium cyanate (3.94 g, 48.6 mmol) in water (30 mL) wasadded during 15 min. to suspension of 2-aminophenol (2.41 g, 22.1 mmol)in 50% aqueous acetic acid (160 mL). The resulting solution was allowedto stand at room temperature overnight and then extracted with ethylether (3 times). The combined organic extracts was concentrated to smallvolume and poured into cold saturated aqueous sodium hydrogen carbonate.The solid was filtered and washed with water to afford the subtitlecompound (1.61 g, 47.9%).

¹H-NMR (400 MHz, DMSO-d₆): δ 9.88 (s, 1H), 7.97 (s, 1H), 7.80 (bd, 1H),6.77 (m, 1H), 6.68 (m, 1H), 6.17 (s, 2H).

ii) N-[2-(2-Oxiranylmethoxy)phenyl]urea

A solution of epibromohydrin (0.94 g, 6.84 mmol) in dry DMF (2 mL) wasadded dropwise to a stirred suspension of N-(2-hydroxyphenyl)urea (0.65g, 4.27 mmol) and cesium carbonate (2.22 g, 6.84 mmol) in DMF (8 mL).After 2 hours the mixture was partitioned between water and ethylacetate. The aqueous phase was extracted with ethyl acetate and thecombined organic phase was washed with water (3 times), dried andconcentrated. The semi-solid residue was disssolved indichloromethane/ethyl ether, filtered and heptane was added toturbidity. After standing at room temperature overnight, the solid wasfiltered to afford the subtitle compound (0.28 g, 32%).

¹H-NMR (400 MHz, DMSO-d₆): δ 8.07(m, 1H), 7.82 (s, 1H), 6.97 (m, 1H),6.85 (m, 2H), 6.24 (bs, 2H), 4.37 (dd, 1H, J=2.5 and 11.6 Hz), 3.89 (dd,1H, J=6.4 and 11.6 Hz), 3.38 (m, 1H), 2.87 (t, 1H, J=4.6 Hz), 2.75 (dd,1H, J=2.6 and 5.2 Hz).

APCI-MS: m/z 209 [MH⁺].

iii)1-(3-{2-[(Aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(4-chlorophenoxy)pyrrolidinium2,2,2-trifluoroacetate

A solution of N-[2-(2-oxiranylmethoxy)phenyl]urea (78 mg, 0.37 mmol) and3-(4-chlorophenoxy)pyrrolidine (70 mg, 0.36 mmol) in absolute ethanol (4mL) was heated at reflux for 2.5 hours. The mixture was thenconcentrated and the residue was purified by HPLC to afford the titlecompound (102 mg, 54.5%).

¹H-NMR (400 MHz, DMSO-d₆+D₂O): δ 7.98 (bd, 1H, J=7.2 Hz), 7.36 (d, 2H,J=8.8 Hz), 6.95-7.02 (m, 3H), 6.88 (m, 2H), 5.15 (bd, 1H), 4.26 (m, 1H).The remaining 10 aliphatic protons appear as complicated overlappingmultiplets between δ 2.04 and 4.04.

APCI-MS: m/z 406 [MH⁺] and 408 [MH⁺+2] for the free base.

EXAMPLE 2131-(3-{2-[(Aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(3,4-dichlorophenoxy)pyrrolidinium2,2,2-trifluoroacetate

A solution of N-[2-(2-oxiranylmethoxy)phenyl]urea (Described underexample 22, step ii; 69 mg, 0.33 mmol) and3-(3,4-dichlorophenoxy)pyrrolidine (77 mg, 0.33 mmol) in absoluteethanol (4.5 mL) was heated at 70° C. for 2 hours. The residue afterevaporation of the solvent was purified by HPLC to afford the titlecompound (133 mg, 72.3%).

¹H-NMR (400 MHz, DMSO-d₆+D₂O): δ 7.96 (bd, 1H, J=7.4 Hz), 7.54 (bd, 1H,J=9.0 Hz), 7.27 (bs, 1H), 6.84-7.00 (m, 4H), 5.20 (bd, 1H), 4.26 (m,1H). The remaining 10 aliphatic protons appear as complicatedoverlapping multiplets between δ 2.05 and 4.03.

APCI-MS: m/z 439.9 [M] and 442 [M+2] for the free base.

EXAMPLE 2141-(3-{2-[(Aminocarbonyl)amino]-4-chlorophenoxy}-2-hydroxypropyl)-3-(4-chlorophenoxy)pyrrolidinium2,2,2-trifluoroacetate

A solution of N-[2-(2-oxiranylmethoxy)phenyl]urea (described underExample 212, step ii; 47 mg, 0.22 mmol) and3-(4-chlorophenoxy)pyrrolidine (41 mg, 0.2 mmol) in absolute ethanol (3mL) was heated at 70° C. for 1.5 hours. The solvent was then evaporatedand the residue was purified by HPLC to afford the title compound (67mg, 60.9%).

¹H-NMR (400 MHz, CD₃OD): δ 8.04(s, 1H), 7.31 (d, 2H, J=8.6 Hz),6.94-6.98 (m, 4H), 5.20 (bs, 1H), 4.40 (m, 1H). The remaining 10aliphatic protons appear as complicated overlapping multiplets between δ2.25 and 4.13.

APCI-MS: m/z 440.1 [M] and 442.1 [M+2] for the free base.

EXAMPLE 215N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N′-ethylureahydrochloride

An ether solution ofN-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)urea[obtained from the hydrochloride (110 mg, 0.25 mmol) by treatment with1M NaOH and extraction with ether] was treated with ethyl isocyanate (16μl, 0.2 mmol) in a sealed vial for 15 h at ambient temperature. Afterevaporation and purification by flash chromatography on silica(EtOAc/MeOH 100/5) the appropriate fractions were acidified with 1M HCland lyophilized from acetic acid to give the title compound as a whiteamorphous solid (35 mg, 37%). The substance is a mixture of twodiastereomeric pairs.

APCI-MS: m/z 434 [MH⁺]

EXAMPLE 216N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N′-methylureahydrochloride

To a solution ofN-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)urea[obtained from the hydrochloride (44 mg, 0.1 mmol) by treatement with 1MNaOH and extraction with ether] in DCM (3 ml) di(tert-butyl)tricarbonate (26 mg, 0.1 mmol) was added, and the solution was set asidefor 15 min. Methylamine (2M in DCM, 100 μl, 0.2 mmol) was added and thesolution was left to stand over night. After evaporation the crudeproduct was purified by preparative RP-HPLC using acetonitrile and watercontaining 0.1% TFA as mobil phase. The appropriate fraction wasconcentrated in vacuo and extracted with 1M NaOH and ether. The residuefrom the organic phase was acidified with 1M HCl and lyophilized fromacetic acid to afford the title compound as a white amorphous solid (15mg, 30%). The substance is a mixture of two diastereomeric pairs.

APCI-MS: m/z 420 [MH⁺]

EXAMPLE 217(2S,4S)-1-{3-[2-(Acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylicacid; compound with trifluoroacetic acid (i) Methyl(2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylatehydrochloride

Methyl (2S,4S)-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylate (370 mg, 1.0mmol) and N-[2-(2-oxiranylmethoxy)phenyl]acetamide (207 mg, 1.0 mmol)dissolved in tert-butanol (7 ml) was stirred in a sealed vial at 100° C.over night. Workup of the crude material by flash chromatography onsilica (DCM/MeOH 100/2), acidification of the appropriate fractions with1M HCl and lyophilization from acetic acid afforded the subtitledcompound as a white amorphous solid (360 mg, 72%). The substance is adiastereomeric mixture.

APCI-MS: m/z 463 [MH⁺]

ii)(2S,4S)-1-{3-[2-(Acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylicacid; compound with trifluoroacetic acid

Compound (i) (50 mg, 0.1 mmol) was dissolved in acetonitrile (2 ml) andwater (3 ml). Lithium hydroxide hydrate (8 mg, 0.2 mmol) dissolved inwater (0.5 ml) was added. The reaction was complete after 0.5 h asdetermined by analytical HPLC. The mixture was acidified with TFA andpurified by preparative RP-HPLC using acetonitrile and water containing0.1% TFA as mobile phase. The appropriate fraction was concentrated invacuo and the residue lyophilized from acetic acid to give the titlecompound as a white amorphous solid (27 mg, 48%). The substance is adiastereomeric mixture.

APCI-MS: m/z 449 [MH⁺], 431 [MH⁺, lactone, minor amount]

EXAMPLE 218 Ethyl(2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(3,4-dichlorophenoxy)-2-pyrrolidinecarboxylate;trifluoroacetic acid salt i) Methyl(2S,4S)-4-(3,4-dichlorophenoxy)-2-pyrrolidinecarboxylate

The compound was prepared by analogy with Example 217(ii) fromN-Boc-cis-4-hydroxy-L-proline methylester and 3,4-dichlorophenol.

¹H-NMR (400 MHz, DMSO-d₆): δ 9.64 (bs, 2H); 7.58 (d, 1H); 7.25 (d, 1H);6.94 (dd, 1H); 5.24 (m, 1H); 4.66 (dd, 1H); 3.76 (s, 3H); 3.55 (dd, 1H);3.47 (d 1H); 2.67-2.58 (m, 1H); 2.38 (d, 1H)

APCI-MS: m/z 290, 292 [MH⁺, isotope pattern]

ii) Ethyl(2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(3,4-dichlorophenoxy)-2-pyrrolidinecarboxylate;trifluoroacetic acid salt

The compound was prepared by analogy with Example 217 from compound i)(404 mg, 1.0 mmol) and N-[2-(2-oxiranylmethoxy)phenyl]acetamide (207 mg,1.0 mmol), with the exception that ethanol was used as solvent.Reesterification occurred, and after work-up and purification the titlecompound was isolated as a white solid (209 mg, 33%). The substance is adiastereomeric mixture.

APCI-MS: m/z 511, 513 [MH⁺, isotope pattern]

EXAMPLE 219N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide;trifluoroacetic acid salt andN-[2-({(2R)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide;trifluoroacetic acid salt i)[(2S,4S)-4-(4-Chlorophenoxy)pyrrolidinyl]methanol

Methyl (2S,4S)-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylate (preparedfrom cis-4-hydroxy-L-proline methylester according to Example 217ii))(850 mg, 3.32 mmol) in dry THF (20 ml) was added during 40 min to amixture of lithium aluminiumhydride (505 mg, 13.3 mmol) in dry THF (10ml) at 0° C. under an argon atmosphere. After stirring overnight at roomtemperature sodium sulfate decahydrate (1 g) was added, followed bydropwise addition of water (0.5 ml), sodium hydroxide (15% w/v, 0.5 ml)and water (1.5 ml). Filtration and evaporation gave a syrup which waspurified by flash chromatography on silica gel(dichloromethane/methanol/concentrated ammonia 100/20/1) to give thesubtitle compounds (0.60 g, 79%).

¹H-NMR (400 MHz, CDCl3): δ 7.22 (m, 2H), 6.78 (m, 2H), 4.79 (m, 1H),3.62 (m, 2H), 3.39 (m, 1H), 3.23 (bd, 1H), 3.14 (dd, 1H, J 5.0 Hz, 12.2Hz), 2.28 (m, 1H), 1.72 (m, 1H).

MS-APCI+: m/z 228 [MH⁺]

ii)N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide;trifluoroacetic acid salt andN-[2-({(2R)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide;trifluoroacetic acid salt

[(2S,4S)-4-(4-Chlorophenoxy)pyrrolidinyl]methanol (380 mg, 1.67 mmol)and N-[2-(2-oxiranylmethoxy)phenyl]acetamide (414 mg, 2.00 mmol) weredissolved in tert-butanol (5 ml) and stirred in a sealed vial at 100° C.for 3 h. The solution was concentrated and the residue was purified byflash chromatography on silica gel (dichloromethane/methanol 13/1)followed by preparative RP-HPLC using acetonitrile/water containing 0.1%trifluoroacetic acid as mobile phase. The appropriate fractions werelyophilized to give the title compounds (epimer A: 248 mg, 27%, epimerB: 115 mg, 13%; stereochemistry at epimeric centre not determined).

Epimer A:

1H-NMR (400 MHz, MeOD): δ 7.82 (dd, 1H, J 1.3 Hz, 8.0 Hz), 7.31 (m, 2H),7.14 (m, 1H), 7.04 (m, 1H), 6.96 (m, 3H), 5.20 (m, 1H), 4.40 (m, 1H),4.11 (bd, 2H), 3.79-4.05 (m, 5H), 3.73 (dd, 1H, J 5.2 Hz, 12.5 Hz), 3.43(dd, 1H, J 2.6 Hz, 13.0 Hz), 2.80 (m, 1H), 2.18 (s, 3H), 2.12 (m, 1H).

MS-APCI+: m/z 435 [MH⁺]

Epimer B:

1H-NMR (400 MHz, MeOD): δ 7.79 (dd, 1H, J 1.3 Hz, 7.9 Hz), 7.32 (m, 2H),7.14 (m, 1H), 7.04 (m, 1H), 6.97 (m, 3H), 5.18 (m, 1H), 4.49 (m, 1H),3.83-4.19 (m, 7H), 3.69 (dd, 1H, J 4.8 Hz, 13.2 Hz), 3.34 (m, 1H), 2.72(m, 1H), 2.18 (s, 3H), 2.07 (m, 1H).

MS-APCI+: m/z 435 [MH⁺]

EXAMPLE 220N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxy-2-methylpropoxy}phenyl)acetamidehydrochloride i) N-{2-[(2-Methyl-2-propenyl)oxy]phenyl}acetamide

The compound (1.74 g, 85%) was prepared from 3-chloro-2-methylpropene(1.09 g, 11.9 mmol) and 2-acetamidophenol (1.50 g, 9.92 mmol)analogously to that described in Example 8(i).

¹H-NMR (400 MHz, CDCl3): δ 8.36 (dd, 1H, J 1.7 Hz, 7.8 Hz), 7.80 (bs,1H), 6.98 (m, 2H), 6.87 (dd, 1H, J 1.6 Hz,), 5.08 (s, 1H), 5.04 (s, 1H),4.51 (s, 2H), 2.21 (s, 3H), 1.85 (s, 3H).

ii) N-{2-[(2-Methyl-2-oxiranyl)methoxy]phenyl}acetamide

The compound (0.56 g, 65%) was prepared fromN-{2-[(2-methyl-2-propenyl)oxy]phenyl}acetamide (800 mg, 3.90 mmol) andm-chloroperbenzoic acid (80%, 1.10 g, 5.22 mmol) analogously to thatdescribed in Example 8 (ii).

¹H-NMR (400 MHz, CDCl3): δ 8.36 (m, 1H), 8.01 (bs, 1H), 7.01 (m, 2H),6.91 (m, 1H), 4.07 (m, 2H), 2.96 (d, 1H, J 4.8 Hz), 2.79 (d, 1H, J 4.8Hz), 2.22 (s, 3H), 1.49 (s, 3H).

iii)N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxy-2-methylpropoxy}phenyl)acetamidehydrochloride

The title compound (255 mg, 110%) was prepared fromN-{2-[(2-methyl-2-oxiranyl)methoxy]phenyl}acetamide (123 mg, 0.557 mmol)and 3-(4-chlorophenoxy)pyrrolidine (100 mg, 0.506 mmol) analogously tothat described in Example 1 (iii).

¹H-NMR (400 MHz, MeOD): δ 7.61 (m, 1H), 7.29 (m, 2H), 7.18 (m, 1H), 7.10(m, 1H), 6.96 (m, 3H), 5.18 (m, 1H), 3.91-4.22 (m, 4H), 3.37-3.76 (m,4H), 2.66 (m, ½H), 2.37 (m, 1H), 2.25 (m, ½H), 2.15 (m, 3H), 1.45 (m,3H).

MS-APCI+: m/z 419 [MH⁺]

General Procedures and Preparation of Starting Materials for Examples221-230

Preparation of the epoxides:

A) N-(2-{[(2S*,3S*)-3-Methyloxiranyl]methoxy}phenyl)acetamide i)N-{2-[(E)-1-Propenyloxy]phenyl}acetamide

A heterogenic mixture of commercially available 1-chloro-2-butene(Aldrich, predominantly trans) (453 mg, 0.49 mL, 5.00 mmol),2-acetamidophenol (756 mg, 5.00 mmol) and potassium carbonate (691 mg,5.00 mmol) in aceton (10 ml) was heated to reflux over night. Afterevaporation of the solvent the residue was taken up by ethylacetate andwater. Washing of the organic phase with water, 5-proz. sodium hyroxideand brine and evaporation of the solvent afforded the crude which waspurified by flash chromatography on silica gel (heptane/EtOAc=3:2).Yield: 732 mg (71%) of a brownish yellow solid. Trans:cis=81:19 (ratiodetermined by ¹H-NMR; 400 MHz, CDCl₃):

MS-APCI+: m/z 206.1 [MH+].

ii) M-chloroperbenzoic acid (70-proz.; 270 mg, 1.92 mmol, 2.0 equiv.)was added to a ice bath cooled solution of compound i) (112 mg, 546μmol) dissolved in dichloromethane (3 ml) and stirred without furthercooling over night. After addition of ethylacetate the mixture waswashed with sat. sodium sulfite, 5-proz. sodium hyroxide and brine.Drying over sodium sulfate, evaporation of the solvent and flashchromatography on silica gel afforded 86 mg (71%) of the product as abeige solid in a trans:cis-ratio of 83:17 as determined by ¹H-NMR.

¹H-NMR (400 MHz, CDCl₃; only the signals of the major isomer are given):δ 8.35 (1H, m), 7.90 (1H, br.s), 7.00 (2H, m), 6.88 (1H, m), 4.30 (1H,dd, J 11.4, 2.5 Hz), 3.96 (1H, dd, J 11.4, 5.7 Hz), 3.08 (2H, m), 2.21(3H, s), 1.40 (3H, d, J 5.2 Hz).

MS-APCI+: m/z 222.1 [MH+].

B) N-(2-{[(2S,3R)-3-Methyloxiranyl]methoxy}phenyl)acetamide i)N-[2-(2-Butynyloxy)phenyl]acetamide

A mixture of 1-bromo-2-butine (1.39 g (10.4 mmol), 2-acetamidophenol(1.58 mg, 10.4 mmol), anhydrous potassium carbonate (1.44 g, 10.4 mmol)and sodium iodide (30 mg) in butanone (50 ml) was heated over night toreflux. After that the reaction mixture was filtrated, the filtrate wasevaporated and the resulting residue was taken up by ethyl acetate. Theobtained solution was washed with 5-proz. sodium hydroxide, brine andwater, dried over sodium sulfate and evaporated. The crude wasrecrystallized out of heptane/MTB (1:1) yielding in 1.57 g (74%) of alight brown needles.

MS-APCI+: m/z 204.1 [MH+].

ii) N-{2-[(Z)-2-Butenyloxy]phenyl}acetamide

A mixture of the alkyne i) (357 mg, 1.76 mmol) and 5-% Pd/BaSO₄ (22 mg)in pyridine (2.0 mL) was hydrogenated for 2 h 30 min under atmosphericpressure at room temperature. At this point the starting material wascompletely consumed, but some overreduction to the corresponding alkanewas observed by LC/MS. The reaction mixture was filtered on celite whichwas thoroughly washed with ethylacetate. Thereafter the filtrate waswashed with 1 N HCl to acidic reaction and finally washed neutral withbrine. Drying over sodium sulfate, evaporation of the solvent yielded in318 mg (88%) crude which contained beside the desired Z-olefin also someE-olefine and corresponding alkane as biproducts. The ratio asdetermined by ¹H-NMR (400 MHz, CDCl₃) was E:Z:alkane=83:10:7. The crudewas used in the next step without further purification.

MS-APCI+: m/z 206.1 [MH+].

iii) The olefine ii) (310 mg, 1.51 mmol) was dissolved indichloromethane (10 ml) and m-chloroperbenzoic acid (80-proz.; 587 mg,2.72 mmol, 1.8 equiv.) was added at 0° C. Stirring over night at ambienttemperature was followed by evaporation of the solvent and taking up theresulting residue with ethylacetate, washing with sat. sodium sulfite,5-% sodium hydroxide and brine and drylng over sodium sulfate.Evaporation of the solvent and flash chromatography on silica gel(ethylacetate/heptane=2:1 continued to ethylacetate) gave 269 mg (81%)of the epoxide in a E:Z-ratio of 82:18 (determined by ¹H-NMR) as a whitepowder.

¹H-NMR (400 MHz, CDCl₃; only the signals of the major isomer are given):δ 8.37 (1H, dd, J 7.5, 2.1 Hz), 7.81 (1H, br.s), 7.02 (2H, m), 6.91 (1H,dd, J 7.4, 1.7 Hz), 4.32 (1H, dd, J 11.1, 3.6 Hz), 4.03 (1H, dd, J 11.1,6.9 Hz), 3.33 (1H, dt, J 7.0, 4.0 Hz), 3.24 (1H, dt, J 9.9, 5.5 Hz),2.21 (3H, s), 1.38 (3H, d, J 5.7 Hz).

MS-APCI+: m/z 222.1 [MH+].

C) N-{2-[(1R,2S,5R)*-6-Oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide i)(2-Cyclopenten-1-yloxy)(triisopropyl)silane

A solution of 2-cyclopentenol (K. Alder, F. H. Flock, Chem. Ber. 1956,89, 1732.) (2.31 g, 27.5 mmol), (triisopropyl)chlorsilane (5.30 g, 5.9mL, 27.5 mmol), imidazole (2.06 g, 30.2 mmol) in DMF (50 mL) was stirredat room temperature for 3 h and for an additional hour at 50° C. Thenthe solution was diluted with ethylacetate, washed 4 times with waterand dried over sodium sulfate. Evaporation of the solvent yielded in6.32 g (96%) of the silylether 513/13 as a colourless liquid. No majorimpurities were visible in the ¹H-NMR-spectrum.

¹H-NMR (400 MHz, CDCl₃): δ 5.88 (1H, m), 5.76 (1H, m), 4.98 (1H, m),2.48 (1H, m), 2.27-2.17 (2H, m), 1.70 (1H, m), 1.12-1.05 (21H, m).

ii) Triisopropyl[(1R,2R,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]silane

M-chloroperbenzoic acid (70-%.; 5.41 g, 21.9 mmol, 1.7 equiv.) was addedto a ice bath cooled solution of compound i) (3.10 g, 12.9 mmol)dissolved in dichloromethane (25 ml) and stirred without further coolingadditional 90 min. After filtration of the reaction mixture, evaporationof the filtrate the residue was dissolved in ethylacetate, washed withsat. sodium sulfite, 5-proz. sodium hydroxide and brine and dried oversodium sulfate. Evaporation of the solvent afforded the crude as amixture of the diastereomeric epoxides in trans/cis-ratio of 78:22(¹H-NMR). Separation by flash chromatography on silica gel(heptane/ethylacetate=95:5 continued to 90:10) afforded 1.65 g (50%) ofthe desired trans-epoxide (1R,2R,5R)* as the first eluated diastereomer.The total yield of both diastereomeric epoxides was 2.86 g (87%).

¹H-NMR (400 MHz, CDCl₃): δ 4.39 (1H, d, J 3.4 Hz), 3.54 (1H, d, J 2.5Hz), 3.37 (1H, d, J 2.5 Hz), 1.94 (1H, m), 1.84 (dtd, J 13.7, 9.3, 1.1Hz), 1.60-1.55 (2H, m), 1.13-1.04 (21H, m).

iii) (1S,2R,5R)*-6-Oxabicyclo[3.1.0]hexan-2-ol

To a solution of the silylether ii) (280 mg, 1.09 mmol) in THF (2.0 mL)tetrabutylammonium fluorid (1.0 M in THF; 1.2 mL, 1.20 mmol) was added.After stirring for 3 h at room temperature the mixture was diluted withethylacetate, washed with brine and dried over sodium sulfate.Chromatographic filtration on silica gel (heptane/tertbutylmethylether2:1 continued to ethylacetate) afforded 79 mg (72%) as a pale yellowoil.

¹H-NMR (400 MHz, CDCl₃): δ 4.36 (1H, d, J 5.1 Hz), 3.55 (1H, s), 3.42(1H, d, J 1.5 Hz), 1.99 (1H, m), 1.84 (1H, dddd, J 13.9, 10.1, 9.0, 1.1Hz), 1.69-1.53 (3H, m).

iv) The title compound was prepared according to the general protocol(I) below.

¹H-NMR (400 MHz, CDCl₃): δ 8.38 (1H, m), 7.91 (1H, br.s), 7.02-6.98 (2H,m), 6.94 (1H, m), 4.78 (1H, td, J 8.0, 1.2 Hz), 3.61 (1H, m), 3.54 (1H,d, J 2.7 Hz), 2.21 (3H, s), 2.21 (1H, m), 2.10 (1H, dt, J 12.8, 12.0Hz), 1.76 (1H, dtd, J 14.3, 10.4, 1.4 Hz), 1.58 (1H, m).

MS-APCI+: m/z 234.1 [MH+].

General Protocol (I) for the Preparation ofN-{2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamides

Step 1—Mitsunobu Coupling:

To a ice bath cooled solution of the epoxyalcohol 546/16 (1.0 equiv.),triphenylphosphine (1.2 equiv.) and a 2-nitrophenol (1.0 equiv.) in dryTHF (2 mL/mmol) diethyl diazodicarboxylic acid (1.2 equiv.) was addeddropwise. Stirring was continued over night without further cooling.Aqueous, basic workup, followed by flash chromatography on silica gel(typical eluant:heptane/ethyl acetate=1:1) afforded the 2-nitrophenolicesters which contained often an equimolar amount of the biproductdiethyl 1,2-hydrazinedicarboxylate.

Step 2—Hydrogenation:

A mixture of 2-nitrophenolic esters as obtained from step 1,diisopropyl(ethyl)amine (2.0 equiv.), acetic acid anhydrate (2.0 equiv.)and 5-proz. Pt/C (10 mg/mmol) in ethyl acetate (10 mL/mmol) washydrogenated for 1 h under atmospheric pressure at room temperature. Inthe case of non-halogenated aromates Pd/C and shorter reaction times,typically about 5 min, could be applied. Thereafter the catalysator wasfiltered off by a celite filled filterfunnel and washed with ethanol.The filtrate was evaporated and the remaining residue was subjected anaqueous, basic work-up. Subsequent flash chromatography on silica gel(typical eluant:ethyl acetate/heptane=2:1) afforded the respectiveacetamides in typical yields of 50-70% (2 steps).

D)N-{5-Chloro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide

Preparation according to protocol (I).

¹H-NMR (400 MHz, CDCl₃): δ 8.47 (1H, d, J 2.5 Hz), 7.89 (1H, br.s), 6.97(1H, dd, J 8.8, 2.5 Hz), 6.85 (1H, d, J 8.8 Hz), 4.74 (1H, td, J 8.0,1.3 Hz), 3.58 (1H, m), 3.56 (1H, m), 2.21 (1H, m), 2.21 (3H, s), 2.09(dt, J 13.0, 7.4 Hz), 1.76 (1H, dtd, J 14.3, 10.1, 1.3 Hz), 1.56 (1H,m).

MS-APCI+: m/z 268.0 [MH+].

E)N-{4-Fluoro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide

Preparation according to protocol (I).

¹H-NMR (400 MHz, CDCl₃): δ 8.23 (1H, dd, J 10.7, 2.8 Hz), 7.99 (1H,br.s), 6.89 (1H, dd, J 9.0, 5.5 Hz), 6.69 (1H, ddd, J 11.1, 9.0 3.1 Hz),4.70 (1H, t, J 7.8 Hz), 3.56 (2H, s), 2.21 (1H, dd, J 14.7, 8.4 Hz),2.21 (3H, s), 2.08 (1H, dt, J 13.0, 8.2 Hz), 1.75 (1H, dtm, J 14.3, 9.5Hz).

MS-APCI+: m/z 252.1 [MH+].

General Protocol (II) for the Addition of Aminocycles to Substituted2-(aryloxymethyl)oxiranes

Equimolar amounts of aminocycle and epoxide, dissolved in a saturatedsolution of LiClO₄ in acetonitrile (1 ml/100 μmmol), were heated to 100°C. in a sealed tube. Typical reaction times ranged from 3 h for openchained epoxides to 18 h for oxabicyclo[3.1.0]hexanes. After coolingdown to ambient temperature the reaction mixture was diluted with ethylacetate and subjected to an aqueous work-up. The crude products wereusually obtained in quantitative ylelds and were purified by flashchromatography on silica gel (typical eluants:ethylacetate/methanol=80:20).

The Examples 221-230 below were prepared according to the generalprotocols (I) and (II).

EXAMPLE 221N-(2-{(1S*,2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide

¹H-NMR (400 MHz, CDCl₃): δ 8.20 (1H, d, J 7.4 Hz), 8.07 (1H, br.s), 7.21(2H, m), 7.01-6.96 (2H, m), 6.92 (1H, dm, J 7.4 Hz), 6.77 (2H, dm, J 8.8Hz), 4.77 (1H, m), 4.54 (1H, br.q, J 4.8 Hz), 4.15 (1H, m), 3.04-2.91(3H, m), 2.81 (1H, q, J 6.8 Hz), 2.62 (1H, quint, J 7.3 Hz), 2.29 (1H,m), 2.16 (3H, s), 2.13-1.90 (5H, m), 1.63 (1H, m).

MS-APCI+: m/z 431.2 [MH+].

EXAMPLE 222N-(2-{(1R*,2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide

¹H-NMR (400 MHz, CDCl₃): δ 8.26 (1H, m), 7.90 (1H, br.d, J 9.5 Hz), 7.20(2H, m), 6.97 (2H, m), 6.88 (1H, br.d, J 7.3 Hz), 6.76 (2H, m), 4.76(1H, m), 4.50 (1H, m), 4.21 (1H, dt, J 14.1, 5.5 Hz), 3.00-2.89 (3H, m),2.67-2.54 (2H, m), 2.28 (1H, m), 2.15 (3H, s), 2.11 (1H, m), 1.97 (2H,m), 1.87 (2H, m).

MS-APCI+: m/z 431.2 [MH+].

EXAMPLE 223N-(2-{(2R*,3R*)-3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-butoxy}-phenyl)-acetamide

¹H-NMR (400 MHz, CDCl₃): δ 8.27 ((1H, dd, J 7.6, 1.6 Hz), 8.07 (1H,br.s), 7.30 (1H, d, J 8.8 Hz), 7.04-6.92 (4H, m), 6.74 (1H, dd, J 8.8,2.9 Hz), 4.26 (1H, m), 4.23 (1H, dd, J 9.9, 2.7 Hz), 4.06 (1H, m), 3.96(1H, dd, J 9.9, 8.0 Hz), 2.86-2.72 (3H, m), 2.58 (1H, m), 2.47 (1H, m),2.18 (3H, s), 1.99 (2H, m), 1.80 (2H, m), 1.12 (3H, d, J 6.9 Hz).

MS-APCI+: m/z 469.1 [MH+].

EXAMPLE 224N-(2-{(1S*,2R*,3S*)-3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide

¹H-NMR (400 MHz, CDCl₃): δ 8.26 (1H, m), 8.20 (1H, br.s), 7.19 (2H, m),7.02 (2H, m), 6.95 (1H, m), 6.84 (2H, m), 4.49 (1H, q, J 5.2 Hz), 4.31(1H, m), 4.15 (1H, m), 2.95 (2H, q, J 7.8 Hz), 2.87 (1H, m), 2.51 (2H,br.q, J 10.2 Hz), 2.19 (3H, s), 2.10-1.95 (5H, m), 1.86 (2H, m), 1.60(1H, m).

MS-APCI+: m/z 445.0 [MH+].

EXAMPLE 225N-(2-{(2R*,3S*)-3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-butoxy}-phenyl)-acetamide

¹H-NMR (400 MHz, CDCl₃): δ 8.47 (1H, br.s), 8.36 (1H, dd, J 7.2, 1.3Hz), 7.32 (1H, d, J 9.0), 7.04-6.93 (4H, m), 6.75 (1H, dd, J 9.0, 2.9Hz), 4.34 (1H, m), 4.11 (1H, m), 3.96 (1H, dd, J 10.5, 5.2 Hz), 3.66(1H, m), 3.00-2.80 (2H, m), 2.71 (2H, m), 2.42 (1H, m), 2.19 (3H, s),2.05 (1H, m), 1.94-1.81 (2H, m), 1.08 (3H, d, J 6.7 Hz).

MS-APCI+: m/z 466.9 [MH+].

EXAMPLE 226N-(2-{(2R*,3R*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-butoxy}-phenyl)-acetamide

¹H-NMR (400 MHz, CDCl₃): δ 8.34 (1H, t, J 4.5 Hz), 8.18 (1H, br.s), 7.22(2H, m), 6.99 (2H, m), 6.93 (1H, m), 6.76 (2H, m), 4.78 (1H, m), 4.20(1H, m), 4.07 (1H, dt, J 10.1, 2.9 Hz), 3.95 (1H, dd, J 10.1, 8.2 Hz),3.15 (0.5H, dd, J 10.7, 6.1 Hz), 2.97-2.94 (1.5H, m), 2.89 (0.5H, q, J7.6 Hz), 2.82 (0.5H, dd, J 10.5, 2.5 Hz), 2.73 (0.5H, qm, J 7.5 Hz),2.65 (0.5H, m), 2.58 (1H, m), 2.26 (1H, m), 2.01 (1H, m), 1.09 (3H,appears as dd, J 6.7, 1.7 Hz).

MS-APCI+: m/z 419.1 [MH+].

EXAMPLE 227N-(2-{(2R*,3S*)-3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-butoxy}-phenyl)-acetamide

¹H-NMR (400 MHz, CDCl₃): δ 8.48 (1H, m), 8.37 (1H, m), 7.22 (2H, m),7.04-6.93 (3H, m), 6.77 (2H, m), 4.80 (1H, m), 4.12 (1H, m), 3.97 (1H,dd, J 10.5, 5.3 Hz), 3.65 (1H, m), 3.09 (0.5H, dd, J 10.3, 6.0 Hz),3.06-2.99 (1.5H, m), 2.94 (0.5H, q, J 8.0 Hz), 2.87-2.67 (2.5H, m), 2.25(1H, m), 2.02 (1H, m), 1.05 (3H, appears as dd, J 6.7, 5.2 Hz).

MS-APCI+: m/z 418.9 [MH+].

EXAMPLE 228N-(2-{(1S*,2R*,3S*)-3-[4-(3-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide

¹H-NMR (400 MHz, CDCl₃): δ 8.25 (1H, m), 8.17 (1H, br.s), 7.18 (1H, t, J8.1 Hz), 7.01 (2H, m), 6.97-6.90 (3H, m), 6.79 (1H, dm, J 9.0 Hz), 4.48(1H, q, J 5.5 Hz), 4.34 (1H, hept, J 3.5 Hz), 4.15 (1H, dd, J 7.2, 5.5Hz), 2.95 (2H, q, J 7.4 Hz), 2.87 (1H, m), 2.52 (2H, br.q), J 9.6 Hz),2.19 (3H, s), 2.09-1.94 (6H, m), 1.86 (2H, m), 1.59 (1H, m).

MS-APCI+: m/z 445.1 [MH+].

EXAMPLE 229N-[5-Chloro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide

¹H-NMR (400 MHz, CDCl₃): δ 8.38 (2H, m), 7.31 (1H, d, J 8.7 Hz), 6.99(1H, d, J 8.8 Hz), 6.95 (1H, dd, J 8.8, 2.6 Hz), 6.86 (1H, d, J 8.8 Hz),6.75 (1H, dd, J 8.8, 2.9 Hz), 4.38 (1H, q, J 4.0 Hz), 4.31 (1H, hept, J3.7 Hz), 4.10 (1H, dd, J≈7, 6 Hz), 3.00 (1H, q, J 7.1 Hz), 2.91-2.82(1H, m), 2.53 (2H, m), 2.17 (3H, s), 2.08-1.93 (5H, m), 1.85 (2H, m),1.60 (1H, m).

MS-APCI+: m/z 513.1 [MH+].

EXAMPLE 230N-[4-Fluoro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide

¹H-NMR (400 MHz, CDCl₃): δ 8.58 (1H, br.s), 8.19 (1H, dd, J 10.9, 3.2Hz), 7.31 (1H, d, J 8.8 Hz), 7.00 (1H, d, J 2.9 Hz), 6.89 (1H, dd, J9.0, 5.2 Hz), 6.75 (1H, dd, J 9.0, 2.9 Hz), 6.67 (1H, td, J 8.8, 3.1Hz), 4.35-4.29 (2H, m), 4.09 (1H, dd, J 7.8, 5.0 Hz), 3.04 (1H, q, J 7.8Hz), 2.88 (2H, m), 2.54 (2H, m), 2.18 (3H, s), 2.08 (5H, m), 1.85 (2H,m), 1.61 (1H, m).

MS-APCI+: m/z 497.2 [MH+].

Preparation of Starting Materials for Examples 231-248 A)(S*R*)-1-(3,4-Dichloro-benzyl)-2,5-dimethyl-piperazine

A solution of 1,2-dichloro-4-chloromethyl-benzene (1.1 ml 7.89 mmol) inDMF (5 ml) was added to 2,5-dimethyl-piperazine (1.0 g, 8.77 mmol)dissolved in DMF (25 ml). The reaction was stirred over night, pouredinto a mixture of EtOAc and sodium carbonate (5%). The water phase waswashed twice with EtOAc and the combined organic phase once with brine,and dried over sodium sulfate. After evaporation the crude was dissolvedin methanol. The dibensylated piperazine does not dissolve. The filtratewas filtered through a short silica column, using methanol as eluant andevaporated to give the pure product. Yield 812 mg, 38%.

¹H-NMR (400 MHz, DMSO-d6): δ 7.56 (d, 1H, J 8.1 Hz), 7.52 (d, 1H, J=1.8Hz), 7.20 (dd, 1H, J=8.2, 1.8 Hz), 3.97 (d, 1H, J=14.1 Hz), 3.04 (d, 1H,J=14.2 Hz), 2.76 (dd, 1H, J=11.9, 3.0 Hz), 2.59 (m), 2.48 (dd, 1H,J=11.9, 2.6 Hz), 2.37 (t, 1H, J=10.8 Hz), 2.12 (m), 1.89 (s), 1.57 (t,1H, J=10.4 Hz), 1.00 (d, 1H, J=6.1 Hz), 0.82 (d, 1H, J=6.3 Hz).

APCI-MS: m/z 273 [M⁺]

B) (S*R*)-1-(4-Chloro-benzyl)-2,5-dimethyl-piperazine

Was synthesized in the same way as A) from1-chloro-4-chloromethyl-benzene (1.27 g, 7.89 mmol) and2,5-dimethyl-piperazine (1.0 g, 8.77 mmol) in DMF. Yield 701 mg, 37%.

¹H-NMR (400 MHz, DMSO-d6): δ 7.36 (d, 2H, J=8.4 Hz), 7.30 (d, 2H, J=8.4Hz), 3.97 (d, 1H, J=13.9 Hz), 3.01 (d, 1H, J=13.8 Hz), 2.75 (dd, 1H,J=11.9, 3.0 Hz), 2.57 (m, 1H, J=10.8, 2.6 Hz), 2.47 (dd, 1H, J=10.9, 2.6Hz), 2.36 (dd, 1H, J=11.6, 10.1 Hz), 2.10 (m, 1H), 1.88 (bs, 1H), 1.53(t, 1H, J=10.5 Hz), 1.01 (d, 3H, J=6.1 Hz), 0.80 (d, 3H, J=6.4 Hz).

APCI-MS: m/z 239 [MH⁺]

C) 1-(3,4-Chlorobenzyl)piperazine

3,4-chlorobenzyl chloride (170 mg, 0.872 mmol) was added to a solutionof piperazine (150 mg, 1.74 mmol) and triethyl amine(1 ml) in DMF (10ml) at room temperature. After 2 hrs the solution was concentrated invacuo. The resulting residue was triturated under ether and the obtainedsolid was washed with water and then dissolved in methanol andco-evaporated with toluene to give the product, 89 mg, as a solid.

APCI-MS: m/z 245, 247[MH⁺]

¹HNMR (400 MHz, CD₃OD) δ 7.41 (d, 1H, J=2.0 Hz), 7.37 (d, 1H, J=8.2 Hz),7.13 (dd, 1H, J=8.2, J=2.0 Hz), 3.5 (s, 2H), 3.05 (m, 4H), 2.57 (m, 4H)

D) 1-(4-Chlorobenzyl)piperazine

Was prepared by analogy to C) above.

EXAMPLE 231N-(2-{3-[4-(3,4-Dichlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}-phenyl)acetamidedihydrochloride

A solution of N-acetyl-2-(2,3-epoxypropoxy)aniline (87.53 mg, 0.422mmol) and 1-(3,4-chlorobenzyl)piperazine in ethanol (10 ml 99.5%) wasrefluxed for 3 hrs. The solvent was distilled off under reduced pressureand the resulting residue was purified by silica gel columnchromatography (dichloromethane/methanol 20:1) to give the titlecompound as a gum. Addition of 1.0M ethereal HCl solution gave a whitesolid product 78 mg (40%).

APCI-MS: m/z 452, 454[MH⁺]

¹HNMR (400 MHz, CD₃OD) δ 8.0 (1H, dd, J=1.53 Hz, J=8.01 Hz), 7.5 (1H, d,J=1.91 Hz), 7.45 (1H, d, J=8.2 Hz), 7.23 (1H, dd, J=6.1 Hz, J=2.1 Hz),6.89-7.08(4H, m), 4.15(1H, m), 3.9-4.1(2H, m), 3.48(2H, S)2.45-2.60(10H, m), 2.17(3H, S).

Examples 232-248 were Synthesized According to Example 231 with theStarting Materials A) to D) Above EXAMPLE 232N-(2-{3-[4-(3,4-Dichlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}-4-fluorophenyl)acetamide

APCI-MS: m/z 470[MH⁺]

EXAMPLE 233N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 480[MH⁺]

EXAMPLE 234N-(5-Chloro-2-{3-[4-(3,4-dichlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 486[MH⁺]

EXAMPLE 235N-(5-Chloro-2-{3-[4-(3,4-dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 480[MH⁺]

EXAMPLE 236N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide

APCI-MS: m/z 494[MH⁺]

EXAMPLE 237N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}-4-fluorophenyl)acetamide

APCI-MS: m/z 498[MH⁺]

EXAMPLE 238N-(2-{3[(S*R*)-4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 480[MH⁺]

EXAMPLE 239N-(2-{3[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 446[MH⁺]

EXAMPLE 240N-(5-Chloro-2-{3-[(S*R*)-4-(3,4-dichlorobenzyl)-2,5-dimethylpiperazinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 514[MH⁺]

EXAMPLE 241N-(5-Chloro-2-{3-[(S*R*)-4-(4-chlorobenzyl)-2,5-dimethylpiperazinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 480[MH⁺]

EXAMPLE 2421-(5-Chloro-2-{3-[4-(4-chlorobenzoyl)-1-piperazinyl]-2-hydroxypropoxy}phenyl)-1-ethanone

APCI-MS: m/z 451[MH⁺]

EXAMPLE 243N-(5-Cyano-2-{3-[(S*R*)-4-(3,4-dichlorobenzyl)-2,5-dimethylpiperazinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 505[MH⁺]

EXAMPLE 244N-(2-{3-[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethylpiperazinyl]-2-hydroxypropoxy}-5-cyanophenyl)acetamide

APCI-MS: m/z 471[MH⁺]

EXAMPLE 245N-(5-Chloro-2-{3-[4-(4-chlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}-phenyl)acetamide

APCI-MS: m/z 452[MH⁺]

EXAMPLE 246N-(4-Chloro-2-{3-[4-(4-chlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 460[MH⁺]

EXAMPLE 247N-(2-{3-[4-(4-Chlorobenzoyl)-1-piperazinyl]-2-hydroxypropoxy}-5-cyanophenyl)acetamide

APCI-MS: m/z 457[MH⁺]

EXAMPLE 248N-(2-{3-[4-(4-Chlorobenzoyl)-1-piperazinyl]-2-hydroxypropoxy}-4-methylphenyl)acetamide

APCI-MS: m/z 446[MH⁺]

EXAMPLE 249N-[5-Chloro-2-({(1R,2S,3R)-3-[(3S)-3-(4-chlorophenoxy)pyrrolidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide

MS-APCI+: m/z 464.9 [MH+].

[α]²²=−47.6 (CH₂C₂).

EXAMPLE 250N-{2-[(2S)-(3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-fluorophenyl}acetamide

APCI-MS: m/z 423.1 [M+]

EXAMPLE 251N-[2-({(2S)-3-[(3S)-3-(4-Chlorobenzyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamidehydrochloride i) 3-(4-Chlorobenzyl)pyrrolidine

To a solution of 3-(4-chlorobenzyl)-2-pyrrolidinone (420 mg, 2 mmol) indry THF (25 mL) and under N₂ LAH (190 mg, 5 mmol) was added in portionswith stirring over a period of a couple of minutes. The temperature wasincreased to 60° C. and the stirring continued for 2.5 h. The mixturewas quenched with 200 μL water, 200 μL 5M NaOH and 600 μL water. Thesolid Li- and Al-salts were filtered off and the filtrate was evaporatedto give a colourless oil (387 mg, 99%).

APCI-MS: m/z 196, 198 [MH⁺]

ii)(2S)-1-[3-(4-Chlorobenzyl)-1-pyrrolidinyl]-3-(2-nitrophenoxy)-2-propanol

A solution of compound (i) (387 mg, 2 mmol) and(2S)-2-[(2-nitrophenoxy)-methyl]oxirane (390 mg, 2 mmol) in ethanol (6mL) was refluxed until the reaction was complete (2 h), as determined byLCMS. The solvent was evaporated to give an orange oil (650 mg, 83%)which was used without further purification.

APCI-MS: m/z 391, 393 [MH⁺]

iii)(2S)-1-(2-Aminophenoxy)-3-[3-(4-chlorobenzyl)-1-pyrrolidinyl]-2-propanol

To a solution of compound (ii) (650 mg, 1.67 mmol) in ethanol (10 mL) at60° C. a mixture of tin(II)chloride dihydrate (2.25 g, 10 mmol) and 35%hydrochloric acid (2.5 mL) was added. The temperature increased rapidlyto 75° C. The mixture was stirred at 60° C. for further 30 min. Afterevaporation of the solvent the residue was extracted with 5M NaOH andether. The organic phase was washed with water, dried and evaporated.The residue was purified by RP-HPLC with acetonitrile and watercontaining 0.1% TFA as mobile phase. The appropriate fraction wasevaporated and the residue extracted with 1M NaOH and ether. Thesubtitle compound was obtained from the organic phase as a colourlessoil (400 mg, 66%).

APCI-MS: m/z 361, 363 [MH⁺]

iv) To a solution of compound (iii) (400 mg, 1.1 mmol) in DCM (10 mL)acetic anhydride (200 μL, 2.1 mmol) was added and the mixture was leftovernight. After evaporation the residue was dissolved in methanol and1.5M sodiummethoxid in methanol (2 mL) was added. The mixture was leftfor 2 h, evaporated and taken up in ether and water. A mixture of thetwo diastereomers was obtained from the organic phase. The diastereomerswere separated by HPLC on a chiral column using a mixture of isohexane,2-propanol and methanol as mobile phase. The isolated enantiomers weredissolved in methanol (1 mL), acidified with 1M hydrochloric acid (1mL), diluted with water and lyophilized to give the title compounds aswhite amorphous solids (156 mg and 173 mg). The absolute stereoisomerismwas not assigned.

APCI-MS: m/z 403, 405 [MH⁺]

EXAMPLE 252N-(5-Chloro-2-{3-[3-(4-chloro-benzyl)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamidetrifluoroacetic acid salt i) 3-(4-Chloro-benzyl)-pyrrolidin-2-one

In a flask was added diisopropylamine (3.22 g, 31.8 mmole) and dry THF(60 ml). The content of the flask was kept under nitrogen, and was thencooled to −76° C. To the cool solution was dropwise added n-butyllithium(n-BuLi, 32 mmole, 20 ml, 1.6 M in hexane). After completed addition,the solution was stirred for 10 minutes, and a solution of1-Trimethylsilanyl-pyrrolidin-2-one (5.00 g, 31.8 mmole, preparedaccording to literature methods) in dry THF (5 ml) was added dropwise.The solution was then stirred for an additional 20 minutes and asolution of 4-Chlorobenzyl chloride (5.13 g, 32 mmole) in THF (5 ml) wasadded via a syringe during 5 minutes. The resulting mixture was stirredat −76° C. for 1 hour, and was then allowed to reach the ambienttemperature and was stirred over night. Water (40 ml) was added and themixture was stirred vigorously for 60 minutes. The phases were separatedand the organic phase was washed with brine, and was finally evaporated,giving an oil which crystallized on standing. The solid was trituratedwith heptane:EtOAc 2:1 and was filtered, giving a partly purified solid.The solid was purified on silica (DCM to DCM:MeOH 99:1 to 98:2 to 97:3gradient) giving 1.3 g (20%) of the sub-title compound.

¹H-NMR (400 MHz, CDCl₃) δ: 7.27 (2H, d, J 8.4 Hz); 7.16 (2H, d, J 8.4Hz); 5.43 (1H, bs); 3.31-3.13 (3H, m); 2.74-2.61 (2H, m); 2.20-2.12 (1H,m); 1.88-1.77 (1H, m)

ii) 3-(4-Chloro-benzyl)-pyrrolidine

In a flask was dissolved the compound obtained in a) (0.20 g, 0.95mmole), in dry THF (10 ml). LiAlH₄ (0.17 g, 4.53 mmole) was added insmall portions over 10 minutes. After completed addition, the mixturewas heated to 60° C. for approximately 3 h under nitrogen, and thereaction was monitored by LC-MS, and was quenched after completedreaction. Before quenching, the reaction was allowed to reach theambient temperature, and water (0.160 ml) was added cautiously drop bydrop. NaOH (10% solution in water, 0.16 ml) was added dropwise, andfinally another portion of water (0.48 ml). The mixture was stirred for1 hour and was then filtered. The filtrate was concentrated in vaccuogiving the sub-title compound (0.18 g, 97%) as a colorless oil.

APCI-MS: m/z 196.1 [M+H]

iii)N-(5-Chloro-2-{3-[3-(4-chloro-benzyl)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamidetrifluoroacetic acid salt

The title compound was prepared according to the method described inExample 1 iii) from the compound obtained in ii).

¹H-NMR (400 MHz, DMSO) δ: 9.93-9.62 (1H, m); 9.12 (1H, s); 8.11 (1H, s);7.38 (2H, d, J 8.9 Hz); 7.29-7.23 (2H, m); 7.12-7.02 (2H, m); 6.11-6.02(1H, m); 4.29-4.16 (1H, bs); 4.05-3.95 (1H, m); 3.95-3.87 (1H, m);3.75-3.50 (2H, m); 3.40-3.22 (3H, m); 2.91-2.65 (3H, m); 2.62-2.52 (1H,m); 2.13 (3H, s); 2.11-1.94 (1H, m); 1.81-1.55 (1H, m)

EXAMPLE 253N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methylphenyl)-1-pyrrolidinecarboxamidetrifluoroacetate i) 2-[(5-Methyl-2-nitrophenoxy)methyl]oxirane

A mixture of 5-Methyl-2-nitrophenol (7.7 g, 50 mmol), potassiumcarbonate (13.8 g, 0.1 mmol) and epibromohydrine (8.25 mL, 0.1 mmol) wasdissolved in DMF (100 mL) and stirred 2-3 h at 100° C. under anatmosphere of nitrogen. The mixture was diluted with ether (0.5 L) andextracted with water until pH=7. The organic phase was evaporated andthe residue was purified by flash-chromatography on silica (DCM) to givethe sub-title compound as a yellow solid (8.65 g, 83%).

¹H-NMR (400 MHz, CDCl₃): δ 7.80 (d, 1H); 6.91 (s, 1H); 6.86 (d, 1H);4.39 (dd, 1H); 4.15 (dd, 1H); 3.43-3.37 (m, 1H); 2.93 (dd, 1H); 2.89(dd, 1H); 2.42 (s, 3H)

ii)1-[3-(4-Chlorophenoxy)-1-pyrroldinyl]-3-(5-methyl-2-nitrophenoxy)-2-propanol

A mixture of compound i) (1.05 g, 5.0 mmol) and3-(4-chlorophenoxy)pyrrolidine (988 mg, 5.0 mmol) in ethanol (12 mL) wasrefluxed for 2 h. The solvent was evaporated to give the crude productas an orange oil, which was used without further purification.

APCI-MS: m/z 407, 409 [MH⁺]

iii)1-(2-Amino-5-methylphenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol

To a stirred solution of compound ii) (2.1 g, 5.0 mmol) in ethanol (10mL) tin(II) chloride dihydrate (5.6 g, 25 mmol) in 35% hydrochloric acid(6 mL) was added at 50° C. An exothermic reaction started and thetemperature increased rapidly to 75° C. The mixture was maintained at60° C. for 0.5 h. The cooled mixture was alkalized with 1M sodiumhydroxide (180 mL) and extracted with ether, the organic phase washedwith water, dried and evaporated to give the subtitle compound as a paleyellow oil (1.34 g, 71%).

NMR: Due to a mixture of two diastereomeric pairs integration willresult in parts of protons.

¹H-NMR (400 MHz, CDCl₃): δ 7.23 (d, 2H); 6.77 (d, 2H); 6.67-6.65 (m,1H); 6.64-6.63 (m, 1H); 4.83-4.76 (m, 1H); 4.14-4.06 (m, 1H); 4.01 (d,2H); 3.71 (bs, 2H); 3.41 (bs, 1H); 3.10 (dd, 0.5H); 3.01-2.90 (m,1.75H); 2.87-2.70 (m, 2.7H); 2.66-2.57 (m, 1.5H); 2.28 (h, 1H); 2.25 (s,3H); 2.06-1.95 (m, 1H)

APCI-MS: 377, 379 [MH⁺]

iv)N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methylphenyl)-1-pyrrolidinecarboxamidetrifluoroacetate

A solution of compound (iii) (75 mg, 0.2 mmol) and di(tert-butyl)tricarbonate (53 mg, 0.2 mmol) in DCM (3 mL) was stirred for 1 h atambient temperature. Pyrrolidine (33 μL, 0.4 mmol) was added and thestirring continued for 1 h. The reaction was complete as determined byLCMS. TFA (1 mL) was added and the solution was left for 1 h. Thevolatile parts were evaporated and the crude product purified bypreparative RP-HPLC using acetonitrile and water containing 0.1% TFA asmobile phase. The appropriate fraction was concentrated in vacuo and theresidue lyophilized to give the title compound as a white amorphoussolid (85 mg, 72%).

NMR: Due to a mixture of two diastereomeric pairs integration willresult in parts of protons. Data are from the free base.

¹H-NMR (400 MHz, CDCl₃): δ 8.03 (dd, 1H); 7.24 (d, 2H); 6.94 (bs, 1H);6.82-6.74 (m, 2H); 6.78 (d, 2H); 6.73-6.68 (m, 1H); 4.85-4.76 (m, 1H);4.11-3.94 (m, 3H); 3.52-3.42 (m, 5.6H); 3.11 (dd, 0.5H); 3.05-2.92 (m,0.45H) 2.95 (d, 1H); 2.87-2.72 (m, 2.5H); 2.62-2.52 (m, 1.4H); 2.37-2.21(m, 0.7H); 2.29 (s, 3H); 2.08-1.90(m, 4.6H)

APCI-MS: m/z 474, 476 [MH⁺]

EXAMPLE 254N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-hydroxyphenyl)acetamidetrifluoroacetate

To a stirred solution of the free base of compound Example 265 iii)following (128 mg, 0.29 mmol) in DCM (4 mL) under N₂ 1M boron tribromidein DCM (0.58 mL, 0.58 mmol) was added at ambient temperature. Theheterogeneous mixture was stirred overnight and poured into methanol.After evaporation the crude product was purified by RP-HPLC usingacetonitrile and water containing 0.1% TFA as mobile phase. Theappropriate fraction was lyophilized to give the title compound as awhite amorphous solid (113 mg, 73%).

APCI-MS: m/z 421, 423 [MH⁺]

EXAMPLE 255N-[2-({(2S)-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-fluorophenyl]acetamidetrifluoroacetic acid salt i)(2S)-2-[(5-Fluoro-2-nitrophenoxy)methyl]oxirane

In a flask was added (R)-glycidol (0.994 g, 13.4 mmole) andtriphenylphosphine (3.52 g, 13.4 mmole) and THF (20 ml, dried overmolecular sieves), and 5-fluoro-2-nitrophenol (2.10 g, 13.4 mmole). Themixture was stirred until a homogeneous solution was obtained. Thesolution was cooled in an ice bath and diethylazodicarboxylate (DEAD,2.11 ml, 13.4 mmole) was added dropwise over a few minutes. Aftercompleted addition, the flask was allowed to reach room temperature andstirred for an additional 2 hours. The solvent was removed in vaccuo andto the residue was added chloroform (5-10 ml). The precipitate (PPh₃O)was removed by filtration and the solid was washed with an additionalamount of chloroform (5-10 ml). The filtrate was added to a flash column(SiO₂, Heptane:Ethyl acetate 4:1), and purified to give 2.02 g (71%) ofthe sub-title compound as a crystalline material after concentration ofpure fractions.

¹H-NMR (400 MHz, CDCl₃) δ: 7.97 (1H, dd, J 9.3, 6.0 Hz); 6.86 (1H, dd, J10.0, 2.5 Hz); 6.80-6.74 (1H, m); 4.44 (1H, dd, J 11.4, 2.6 Hz); 4.12(1H, dd, J 11.2, 5.1 Hz); 3.44-3.38 (1H, m); 2.95 (1H, t, J 4.5 Hz);2.90 (1H, dd, J 4.8, 2.6)

ii)(2S)-[4-(3,4-Dichlorophenoxy)-1-pieridinyl]-3-(5-fluoro-2-nitrophenoxy)-2-propanol

In a vial was added 4-(3,4-dichlorophenoxy)-piperidine (0.123 g, 0.5mmole) and the compound obtained in i) (0.106 g, 0.5 mmole) and ethanol(99.5%, 3 ml). The vial was sealed and the content was heated withstirring at 65° C. for 3 hours, and the reaction was monitored on LC-MS.The vial was allowed to cool and the solvent was evaporated, giving anoil, which was purified on silica (DCM to DCM:MeOH 99:1 to 98:2 to 97:3as a stepwise gradient). Evaporation of pure fractions gave 0.22 g (96%)of the sub-title compound as an oil.

APCI-MS (m/z): 459.1 [M+H]

iii)N-[2-({(2S)-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-fluorophenyl]acetamidetrifluoroacetic acid salt

The compound obtained in ii) (0.22 g, 0.48 mmole) was dissolved inethanol (99.5%, 7 ml) and heated with stirring to 60° C. A solution ofSnCl₂×2H₂O (0.56 g, 5 equivalents) in concentrated hydrochloric acid(0.63 ml) was added and was stirred at 60° C. for 1 hour. The mixturewas then allowed to cool. The solution was alkalized by the addition ofexcess 2M NaOH, and the solution was extracted with diethyl ether (3×50ml). The combined ethereal solutions were washed with brine anevaporated. The obtained oil was dissolved in THF (8 ml), and water (8ml) was added, followed by the addition of acetic anhydride (50□l, 0.52mmole). The mixture was stirred at 40° C. for 15 minutes. The organicsolvent was removed in vaccuo, and the residue was extracted with EtOAc(3×30 ml). The combined organic phases were washed with brine and werethen concentrated in vaccuo. The residual oil was purified onpreparative HPLC giving 55 g (20%, 98% purity) of the title compound asthe trifluoro acetate, and as a white solid after lyophilization of purefractions.

APCI-MS (m/z): 471.0, 472.0, 473.0 and 474.0 [M+H]

EXAMPLE 256N-(2-(3-(4-Chloro-phenoxy)-pyrrolidin-1-yl)-2-hydroxy-propoxy)-4,6-difluoro-phenyl)-acetamidehydrochloride i) 3,5-Difluoro-6-nitrophenol

To a stirred solution of 2,3,4-trifluoronitrobenzene (5 g, 28.23 mmol)in dry methanol (70 ml) was added a solution of sodium (0.68, 29.46) indry methanol (30 ml). The solution was stirred until all startingmaterial was consumed (˜2 h). After concentration water was added andthe solution was extracted with ether, dried over Na₂SO₄, filtered andconcentrated to a yellow residue (4.65 g). To the solution of the yellowresidue in dichloromethane (140 ml) was added boron tribromide (1M indichloromethane, 40 ml) and stirred at room temperature overnight. Waterwas then added and the solution stirred for further 30 min. The organicphase was separated and the water phase was extracted with ether. Thecombined organic phase were dried over Na₂SO₄, filtered and concentratedin vacuo to give a brownish residue. The residue was taken up into etherand washed with 2M sodium hydroxide and water. The water and sodiumhydroxide washings were combined and neutralized with 6M HCl andextracted with ether, dried over Na₂SO₄ and evaporated to give a yellowresidue which was purified by flash chromatography on silica gel withEtOAc:Heptan; 1:2 as eluent to give the desired product 2 g, 11.42 mmol.

GC-MS: m/z 175(M+)

¹HNMR (400 MHz, CD₃OD) δppm, 6.63-6.68(1H, m), 6.60-6.67(1H, dt)

ii) 2-[3,5-Difluoro-2-nitrophenoxy)methyl]oxirane

To a mixture of 3,5-difluoro-6-nitrophenol (100 mg, 0.571 mmol) andpotassium carbonate (394 mg) in DMF (5 ml) was added epibromohydrin (80mg, 0.582 mmol) and was stirred at 70° C. for 3 hr. Water and ethylacetate were added, the organic phase separated, dried and concentrated.The resulting residue was purified by chromatography (ethylacetate:heptan 1:3) to give the desired product as a solid 161 mg (0.696mmol).

GC-MS: m/z 231 (M+)

iii)1-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-3-(3,5-difluoro-2-nitrophenoxy)-2-propanol

A solution of 3-(4-chlorophenoxy)pyrrolidine and2-[(3,5-difluoro-2-nitrophenoxy)methyl]oxirane (50 mg, 0.216 mmol) inethanol was refluxed for 3 hrs. The solvent was distilled off underreduced pressure and the resulting residue purified by silica gel columnchromatography (dichloromethane/methanol 20:1) to give 45 mg (0.105mmol) of the title compound as solid.

iv)N-(2-(3-(4-Chloro-phenoxy)-pyrroldin-1-yl)-2-hydroxy-propoxy)-4,6-difluoro-phenyl)-acetamidehydrochloride

Platinum oxide on carbon was added to a solution of1-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-3-(3,5-difluoro-2-nitrophenoxy)-2-propanol(40 mg, 0.0932 mmol) in ethanol and the mixture was hydrogenated for 4hrs at 1 atm. The mixture was filtered through Celite and washed severaltimes with warm ethanol and the combined filtrate were concentrated invacuo. To the resulting yellow residue was taken up in dichloromethaneand acetic anhydride was added to the solution. The solution was stirredat room temperature for 2 hrs then concentrated. Addition of 1.0Methereal hydrogen chloride solution gave the title product as solid 20mg.

APCI-MS: m/z 441 [MH⁺]

EXAMPLE 257N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)-4-fluorophenyl]acetamidetrifluoroacetic acid salt

The title compound was prepared according to the procedure described inExample 260 following.

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.89 (1H, bs); 9.05 (1H, s); 7.79 (1H, dd,J 8.8, 6.6 Hz); 7.37 (2H, d, J 9.6 Hz); 7.00-6.94 (3H, m); 6.75 (1H, dt,J 8.6, 2.6 Hz); 6.00 (1H, bs); 5.17-5.10 (1H, m); 4.32-4.20 (1H, m);4.05 (1H, dd, J 10.1, 4.6 Hz); 3.97 (1H, dd, J 9.9, 5.7 Hz); 3.78-3.50(3H, m); 3.47 (1H, t, J 11.6 Hz); 3.17 (1H, t, J 13.3 Hz); 2.83 (1H, p,J 6.9 Hz); 2.07 (3H, s); 1.90-1.80 (1H, m); 1.42 (3H, d, J 6.4 Hz)

EXAMPLE 258N-[2-({(2S)-3-[(3R)-3-(4-Chlorobenzyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamidehydrochloride

Prepared by the method described in Example 251.

EXAMPLE 259N-{2-[(2R)-(3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-fluorophenyl}acetamide

APCI-MS: m/z 423.1 [M+]

EXAMPLE 260N-[2-({(2S)-3-[(2R,4S)-4-(4-chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamidetrifluoroacetic acid salt i) 1-(tert-Butyl) 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate

In a flask was dissolved (2S,4R)-4-Hydroxy-proline hydrochloride (5.4 g,30 mmole) in a mixture of THF (200 ml), water (170 ml) and NaOH (30 ml,2 M in water, 60 mmole). To this emulsion was addeddi-tert-butyldicarbonate (Boc₂O, 6.54 g, 30 mmole), and the mixture wasstirred vigorously for 1 hour. Ether (100 ml) was added and the phaseswere allowed to separate. The aqueous phase was extracted with anadditional 100 ml of ether. The aqueous phase was discarded and thecombined organic phases were washed with 1M HCl (aq.) and potassiumcarbonate (saturated, aq.) and brine. The extract was dried with Na₂SO₄and was concentrated in vaccuo to give a residue, which was purified onsilica (Heptane:EtOAc 5:1 to 3:1 to 1:1 stepwise gradient, spotsvisualized with I₂/MeOH). Evaporation of pure fractions wereconcentrated in vaccuo to give 4.2 g (57%) of the sub-title compound asa colorless oil.

¹H-NMR (400 MHz, CDCl₃) δ: 4.50 (1H, bs); 4.45-4.35 (1H, m); 3.74 (3H,s); 3.64 (1H, dd, J 11.7, 4.3 Hz); 3.59-3.42 (1H, m); 2.35-2.20 (1H, m);2.14-2.03 (1H, m); 1.97 (1H, dd, J23.3, 3.7 Hz); 1.44 (9H, d, J 18.9 Hz)

ii) 1-(tert-Butyl) 2-methyl (2S,4S)-4-(4-chlorophenoxy)-1,2pyrrolidinedicarboxylate

In a flask was dissolved the compound obtained in i) (2.54 g, 10.3mmole), triphenylphosphine (2.71 g, 10.3 mmole) and 4-Chlorophenol (1.33g, 10.3 mmole) in THF (50 ml, dried over molecular sieves) undermagnetic stirring. The flask was cooled in an ice bath and, to thisstirred solution was added diethylazodicarboxylate (DEAD, 1.8 g, 10.3mmole) dropwise under a few minutes. The reaction was allowed to standover night, allowing the ice to melt and the reaction to reach roomtemperature. The solvents were evaporated and the residue was treatedwith ether (30 ml), allowing the phosphine oxide to precipitate. Thesolid was removed by filtration and the filtrate concentrated in vaccuo.The residue was purified on silica (Heptane:EtOAc 8:1 to 6:1 to 3:1,stepwise gradient. Spots on TLC were visualized by Seebach's reagent).Concentration of pure fractions gave 2.51 g (68%) of the sub-titlecompound as a colorless viscous oil.

¹H-NMR (400 MHz, CDCl₃) δ: 7.26-7.20 (2H, m); 6.77-6.70 (2H, m); 4.86(1H, bs); 4.55 (½H, dd, J 8.6, 2.6 Hz); 4.43 (½H, dd, J 7.6, 3.9 Hz);3.84-3.60 (5H, m); 2.53-2.36 (2H, m); 1.47 (9H, d, J 18.2 Hz)

iii) tert-Butyl(2S,4S)-4-(4-chlorophenoxy)-2-(hydroxymethyl)-1-pyrrolidinecarboxylate

In a flask was dissolved the compound obtained in ii) (0.951 g, 2.67mmole) in THF (10 ml, dried-over sieves). The solution was cooled in anice bath and LiBH₄ (0.09 g, 4.07 mmole) was added. The mixture wasstirred over night, allowing the ice to cool, and the solution to reachroom temperature. The crude mixture was then partitioned between EtOAc(100 ml) and water (100 ml). The aqueous phase was discarded and theorganic solution was washed with 0.5M HCl (aq.), NaHCO₃ (sat, aq) andbrine. The solution was evaporated to give an oil which seem to becontaminated with inorganic salts. Dissolution in DCM and filtrationthrough Celite® afforded 0.82 g (94%) of the sub-title compound as acolorless oil.

¹H-NMR (400 MHz, DMSO-d₆) δ: 7.33 (2H, d, J 9.5 Hz); 6.95 (2H, d, J9.5); 4.96 (1H, bs); 4.71 (1H, bs); 3.84-3.55 (3H, m); 3.32 (2H, bs);2.29-2.07 (2H, m); 1.41 (9H, s)

iv) tert-Butyl(2S,4S)-4-(4-chlorophenoxy)-2-{[(methylsulfonyl)oxy]methyl}-1-pyrrolidinecarboxylate

In a flask was dissolved the compound-obtained in iii) (0.82 g, 2.5mmole) in dichloromethane (10 ml, dried over molecular sieves). Theflask was cooled on ice, and triethylamine (0.69 ml, 5.0 mmole) wasadded from a syringe. Methanesulfonylchloride (0.30 ml, 3.86 mmole) wasadded dropwise over a few minutes, and the obtained mixture was stirredover night, allowing the ice to melt. To the mixture was added DCM (60ml), and the solution was washed with 1M HCl (aq), NaHCO₃ (sat, aq), andbrine. The solution was evaporated giving 0.876 g (86%) of the sub-titlecompound as a yellow oil, which was used in the next step without anyfurther purification.

¹H-NMR (400 MHz, DMSO-d₆) δ: 7.35 (2H, d, J 9.4 Hz); 6.99 (2H, d, J 9.4Hz); 5.07-5.01 (1H, m); 4.37 (1H, dd, J 8.9, 4.2 Hz); 4.20-4.05 (2H, m);3.71 (1H, dd, J 11.8, 5.0 Hz); 3.32 (2H, s); 3.15 (3H, s); 2.07 (1H, d,J 14.4 Hz); 1.41 (9H, s)

v) tert-Butyl(2R,4S)-4-(4-chlorophenoxy)-2-methyl-1-pyrrolidinecarboxylate

In a flask was dissolved the compound obtained in iv) (0.876 g, 2.16mmole) in THF (10 ml, dried over molecular sieves). The reaction mixturewas kept under an inert atmosphere and was then cooled in an ice bath.LiB(Et)₃H (1M Lithium triethylborohydride in THF, 9 ml, 9 mmole) wasadded with a syringe over 15 minutes. The ice bath was removed and themixture was stirred over night. The crude mixture was partitionedbetween EtOAc (100 ml) and water (100 ml). The aqueous phase wasremoved, and the organic phase was washed with 1M HCl (aq.), NaHCO₃(sat, aq), and brine. The solution was evaporated and the residue waspurified on silica (Heptane:EtOAc 10:1 to 5:1 to 4:1 to 2:1 gradient.TLC spots were visualized by Seebach's reagent), giving 0.401 g (60%) ofthe sub-title compound as a colorless oil.

¹H-NMR (400 MHz, DMSO-d₆) δ: 7.33 (2H, d, J 8.7 Hz); 6.96 (2H, d, J 8.7Hz); 5.00-4.94 (1H, m); 3.89 (1H, bs); 3.64 (1H, dd, J 12.5, 5.2 Hz);3.38 (1H, d, J 12.2 Hz); 2.41-2.28 (1H, m); 1.79 (1H, d, J 13.7 Hz);1.40 (9H, s); 1.23 (3H, d, J 6.6 Hz)

vi) (2R,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidine trifluoroacetic acidsalt

In a flask was dissolved the compound obtained in v) (0.390 g, 1.25mmole) in dichloromethane (DCM, 15 ml). To this solution was added TFA(trifluoroacetic acid, 6 ml) and the mixture was allowed to stand for 3hours, after which the volatiles were removed in vaccuo. The residue wasco-evaporated twice with DCM, giving the sub-title compound as an oil.

APCI-MS (m/z): 212 [M+H]

vii)N-[2-({(2S)-3-[(2R,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamidetrifluoroacetic acid salt

The title compound was prepared according to the method outlined inExample 255 starting from the material obtained in vi) and(2S)-2-[(2-nitrophenoxy)methyl]oxirane. The compound was obtained in 25%yield.

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.88 (1H, bs); 9.02 (1H, s); 7.89 (1H, d, J7.7 Hz); 7.37 (2H, d, J 7.7 Hz); 7.09-6.88 (5H, m); 6.02 (1H, bs);5.18-5.11 (1H, m); 4.34-4.22 (1H, m); 4.02 (1H, dd, J 10.2, 4.3 Hz);3.94 (1H, dd, J 9.8, 5.7 Hz); 3.77-3.30 (4H, m); 3.19 (1H, t, J 10.7Hz); 2.84 (1H, p, J 6.7 Hz); 2.09 (3H, s); 1.91-1.81 (1H, m); 1.43 (3H,d, J 6.4 Hz)

APCI-MS (m/z): 419.2 [M+H]

EXAMPLE 261N-{2-[(2S)-(3-{(3R)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-fluorophenyl}acetamide

APCI-MS: m/z 423.1 [M+]

EXAMPLE 262N′-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methylphenyl)-N,N-dimethylureatrifluoroacetate

The title compound was prepared by analogy to the methods described inExample 253 starting from compound iii) (75 mg, 0.2 mmol) anddimethylamine (2M in THF, 200 μL, 0.4 mmol). The substance was obtainedas a white amorphous solid (73 mg, 65%).

¹H-NMR (400 MHz, MeOH-d4): δ 7.54 (dd, 1H); 7.51 (d, 2H); 7.16 and 7.15(d, 2H); 7.05 (bs, 1H); 6.96 (bd, 1H); 5.40-5.35 (m, 1H); 4.54-4.46 (m,1H); 4.27 (d, 2H); 4.16-3.56 (m, 6H); 3.20 (bs, 6H); 2.84-2.59 (m, 1H);2.59-2.44 (m, 1H); 2.50 (s, 3H).

APCI-MS: m/z 448, 450 [MH⁺]

EXAMPLE 263N-(2-{3-[3-(4-Chloroanilino)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamidei) tert-Butyl-3-hydroxy-1-pyrrolidinecarboxylate

To a solution of 3-hydroxy-1-pyrrolidine (871 mg, 10 mmol) in THF (30mL) was added di-(tert.butyl) dicarbonate (2.18 g, 10 mmol) in THF (2mL) and the reaction mixture kept on stirring at room temperature forovernight. The solvent was removed in vacuo and the residue was purifiedby flash chromatography (0-2% MeOH in CHCl₃) to give the subtitledcompound (1.7 g).

¹H-NMR (CDCl₃, 400 MHz): δ 4.45 (m, 1H); 3.55-3.25 (m, 4H); 2.18-1.85(m, 3H); 1.45 (s, 9H).

APCI-MS: m/z 166 (M-Boc).

ii) tert-Butyl-2-oxo-1-pyrrolidinecarboxylate

Chromium (vi) oxide (800 mg, 8.0 mmol) was added to pyridine (1.6 mL) inCH₂Cl₂ (10 mL) and the resulting solution was stirred for 15 min at roomtemperature. A solution of tert.butyl-3-hydroxy-1-pyrrolidinecarboxylate(374.5 mg, 2.0 mmol) in CH₂Cl₂ (5 mL) was added, immediately followed byacetic anhydride and the reaction mixture kept at room temperature for15 min. After addition of ethyl acetate, decanted and filtered through ashort column of silica gel. The filtrate was concentrated to give thesubtitled product (193 mg) and was used directly in the next step.

iii) tert-Butyl-3-(4-chloroanilino)-1-pyrrolidinecarboxylate

Tert.butyl-2-oxo-1-pyrrolidinecarboxylate (190 mg, 1.02 mmol),4-chloroaniline (64 mg, 0.5 mmol) and acetic acid (184 mg) were mixed indichloroethane (5 mL). Sodium triacetoxyborohydride (326.5 mg) was addedand the reaction mixture kept on stirring at room temperature forovernight. After addition of aq. NaHCO₃ the reaction mixture was dilutedby addition of ethyl acetate. Two layers were separated. The organiclayer was dried over Na₂SO₄, filtered, concentrated. The residue waspurified by flash chromatography (0-15% ethyl acetate in petroleumspirit, 40-60) to give the subtitled product (140 mg).

¹H-NMR (CDCl₃, 400 MHz): δ 7.18 (m, 2H); 6.50 (m, 2H); 3.99 (m, 1H);3.70 (m, 2H); 3.46 (m, 2H); 3.20 (m, 1H); 2.18 (m, 1H); 1.87 (m, 1H);1.45 (s, 9H).

APCI-MS: m/z 197 (M-Boc).

iv) N-(4-Chlorophenyl)-3-pyrrolidinamine (2×CF₃COOH)

To a solution of tert.butyl-3-(4-chloroanilino)-1-pyrrolidinecarboxylate(130 mg, 0.438 mmol) in CH₂Cl₂ (5 mL) was added CF₃COOH (1 mL). After 30min the volatiles were removed in vacuo to give the subtitled product(186 mg) and was used directly in the next step.

v)N-(2-{3-[3-(4-Chloroanilino)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide

A mixture of N-(4-chlorophenyl)-3-pyrrolidinamine (2×CF₃COOH), (186 mg,0.438 mmol), N-[2-(2-oxiranylmethoxy)phenyl]acetamide (91 mg, 0.438mmol) and K₂CO₃ (200 mg) in ethanol (6 mL) was kept on stirring at 65°C. for 2.5 h. The volatiles were removed in vacuo. The residue waspartitioned between ethyl acetate and aq. NH₄Cl solution. The organiclayer was washed with water, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography (0-3%MeOH in CHCl₃) to give the titled product (70 mg).

¹H-NMR (CDCl₃, 400 MHz): δ 8.35 (m, 1H); 8.21 (br.s, 1H); 7.12 (m, 2H);7.01 (m, 2H); 6.92 (m, 1H); 6.48 (m, 2H); 4.13-3.92 (m, 4H); 3.84 (br.s, 1H); 2.99 (m, 1H); 2.87-2.30 (m, 6H); 2.18 (s, 3H); 1.66 (m, 1H).

APCI-MS: m/z 446 (MH⁺).

EXAMPLE 264N-{2-[(3-{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-1-methylpropyl)oxy]phenyl}acetamidehydrochloride i) N-{2-[(1-Methyl-2-propenyl)oxy]phenyl}acetamide

The compound (557 mg, 40%) was prepared from 3-chloro-1-butene (747 ml,7.42 mmol) and 2-acetamidophenol (1.02 g, 6.75 mmol) analogously to thatdescribed in Example 8 i).

¹H-NMR (400 MHz, CDCl₃): δ 8.37 (m, 1H), 7.80 (bs, 1H), 6.94 (m, 3H),5.93 (m, 1H), 5.25 (m, 2H), 4.84 (m, 1H), 2.21 (s, 3H), 1.49 (d, J 6.3Hz, 3H).

ii) N-{2-[1-(2-Oxiranyl)ethoxy]phenyl}acetamide

The compound was prepared fromN-{2-[(1-Methyl-2-propenyl)oxy]phenyl}acetamide (549 mg, 2.67 mmol) andm-chloroperbenzoic acid (80%, 923 mg, 4.28 mmol) analogously to thatdescribed in Example 8 (ii). Purification was done on silica gel withpetroleum ether/ethyl acetate 10/15 as eluent. This gave separation ofthe two diastereomeric pairs.

Diastereomer 1: (53 mg, 9%), Rf=0.27

Diastereomer 2: (406 mg, 69%), Rf=0.20

¹H-NMR (400 MHz, CDCl₃): δ 8.39 (m, 1H), 8.01 (bs, 1H), 7.00 (m, 3H),3.98 (m, 1H), 3.24 (m, 1H), 2.94 (t, J 4.5 Hz, 1H), 2.71 (dd, J 2.6 Hz,J 4.5 Hz, 1H), 2.23 (s, 3H), 1.47 (d, J 6.3 Hz, 3H).

iii)N-{2-[(3-{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-1-methylpropyl)oxy]phenyl}acetamidehydrochloride

The title compound (230 mg, 100%) was prepared fromN-[2-(1-oxiranylethoxy)phenyl]acetamide diasteromer 2 (123 mg, 0.557mmol) and 3-(4-chlorophenoxy)pyrrolidine (100 mg, 0.506 mmol)analogously to that described in Example 1 (iii).

¹H-NMR (400 MHz, MeOD): δ 7.86 (m, 1H), 7.30 (m, 2H), 7.09 (m, 2H), 6.97(m, 3H), 5.21 (m, 1H), 4.51 (m, 1H), 3.83-4.22 (m, 3H), 3.37-3.62 (m,4H), 2.68 (m, ½H), 2.38 (m, 1H), 2.27 (m, ½H), 2.19 (m, 3H), 1.32 (m,3H).

MS-APCI+: m/z 419 [MH⁺]

EXAMPLE 265N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methoxyphenyl)acetamidehydrochloride i)1-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-3-(5-methoxy-2-nitrophenoxy)-2-propanol

The subtitle compound was prepared in analogy of Example 253 ii) from2-[(5-methoxy-2-nitrophenoxy)methyl]oxirane (320 mg, 1.6 mmol) and3-(4-chlorophenoxy)pyrrolidine (365 mg, 1.6 mmol). The crude product wasobtained as a yellow oil (580 mg) and was used without furtherpurification.

APCI-MS: m/z 423, 425 [MH⁺]

ii)1-(2-Amino-5-methoxyphenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol

The subtitle compound was prepared in analogy of Example 253 iii) fromcompound i) (290 mg, 0.7 mmol). The crude compound was obtained as acolourless oil (233 mg, 85%) and was used without further purification.

APCI-MS: m/z 393, 395 [MH⁺]

iii)N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methoxyphenyl)acetamidehydrochloride

To a solution of compound (ii) (157 mg, 0.4 mmol) in pyridine (3 mL)acetic anhydride (1 mL) was added. The mixture was stirred for 1 h atambient temperature. After evaporation the residue was dissolved inmethanol (mL) and 1.5M sodium methoxide in methanol (1 mL) was added.The mixture was left overnight at ambient temperature. After evaporationthe residue was taken up in ether and water. The free base of the titlecompound was obtained from the organic phase as a colourless oil (171mg, 98%). The free base (43 mg) was dissolved in methanol (5 mL),acidified with 1M hydrochloric acid till pH<2, diluted with water (50mL) and lyophilized. The title compound was obtained as a whiteamorphous solid (30 mg, 64%).

APCI-MS: m/z 435, 437 [MH⁺]

EXAMPLE 266N-(2-[3-(4-Chloro-benzyloxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy)-phenyl)-acetamidetrifluoroacetic acid salt i)3-(4-Chloro-benzyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester

A solution of tert-butyl 3-hydroxy-1-pyrrolidinecarboxylic acid (0.27 g,1.44 mmol) in dry THF (4 mL) was added dropwise to a cold (0° C.),stirred suspension of sodium hydride (0.078 g, 2.17 mmol, ca. 50%suspension in oil) in THF (10 mL). After 30 min. a solution of4-chlororbenzyl bromide (0.36 g, 1.74 mmol) in THF (2 mL) was added andthe resulting suspension was stirred at R.T. overnight. The reactionmixture was partitioned between water and ethyl acetate. The aqueousphase was extracted with ethyl acetate and the combined organic phasewas washed with saturated aqueous sodium chloride, dried andconcentrated. The residue was subjected to flash chromatography(heptane-ethyl acetate, 6:1) to afford the subtitle compound3-(4-Chloro-benzyloxy)-pyrrlidine-1-carboxylic acid tert-butyl ester asan oil (0.30 g, 66.8%).

¹H-NMR (CDCl₃): δ 7.30 (m, 4H), 4.49 (bs, 2H), 4.11 (m, 1H), 3.45 (m,4H), 1.90-2.08 (m, 2H), 1.46 (s, 9H).

ii) 3-(4-Chloro-benzyloxy)-pyrrolidine

A solution of 3-(4-Chloro-benzyloxy)-pyrrolidine-1-carboxylic acidtert-butyl ester (0.28 g, 0.9 mmol) in aqueous 90% formic acid (7.5 mL)was stirred at (0° C.) for 30 min. then at room temperature overnight.The solvents were removed under reduced pressure and the residue wastreated with saturated aqueous potassium carbonate and extracted twicewith n-butanol. The combined organic extracts was concentrated and theresidue was purified by flash chromatography (SiO₂,dichloromethane-methanol-ammonium hydroxide, 8:8:1 then 50:10:1) toafford the subtitle compound 3-(4-Chloro-benzyloxy)-pyrrolidine (0.13 g,70%).

¹H-NMR (DMSO-d₆): δ 7.32-7.41 (m, 4H), 4.42 (s, 2H), 4.02 (m, 1H), 3.18(bs, 3H), 2.75-2.86 (m, 3H), 2.68 (m, 1H), 1.66-1.81 (m, 2H).

APCI-MS: m/z 212 [MH⁺].

iii)N-(2-[3-(4-Chloro-benzyloxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy)-phenyl)-acetamidetrifluoroacetic acid salt

A solution of 3-(4-chloro-benzyloxy)-pyrrolidine (0.050 g, 0.24 mmol)and N-(2-oxiranylmethoxy-phenyl)-acetamide (0.049 g, 0.24 mmol) inabsolute ethanol (3 mL) was heated in a closed vial at 70° C. for 2 h.The product was purified by HPLC to afford the title compound (0.60 g,47%).

¹H-NMR (CD₃OD): δ 7.85 (m, 1H), 7.35 (m, 4H), 7.12 (m, 1H), 7.02 (d, 1H,J=8 Hz), 6.96 (m, 1H), 4.56 (m, 2H), 4.39 (m, 2H), 4.05 (d, 2H, J=5.9Hz), 3.85 (m, 2h), 3.48 (m, 4H), 2.10-2.55 (m, 5H).

APCI-MS: m/z 419 [MH⁺] and 421 [MH+2⁺].

EXAMPLE 267N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-acetamide

The compound was prepared by a method analogous to that of Example 270following.

APCI-MS: m/z 419 [MH⁺]

EXAMPLE 268N-(2-{(1S,2R,3S)*-3-[(3S)-3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-5-chloro-phenyl)-acetamide(diastereomeric mixture)

Was prepared by analogy to Example 271 following fromN-{5-chloro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide(5.3 mg, 20 μmol) and (3S)-3-(3,4-difluoro-phenoxy)-pyrrolidine (4.0 mg,20 μmol).

MS-APCI+: m/z 467 [M+].

EXAMPLE 269N-[2-({(2R,3S)*-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxybutyl}oxy)-4-methylphenyl]acetamide(diastereomeric mixture)

Was prepared analogies to Example 271 following fromN-(4-methyl-2-{[(2S,3R)*-3-methyloxiranyl]methoxy}phenyl)acetamide (4.7mg, 20 μmol) and (3S)-3-(4-Chloro-phenoxy)-pyrrolidine (4.0 mg, 20μmol).

MS-APCI+: m/z 433 [M+].

EXAMPLE 270N-{2-[(3-{4-[(3,4-Dichlorophenyl)oxy]-1-piperidinyl}-2-hydroxy-2-methylpropyl)oxy]-4-fluorophenyl}acetamidehydrochloride i) N-[4-Fluoro-2-(2-methyl-allyloxy)-phenyl]-acetamide

3-Chloro-2-methylpropene (1.36 g, 15 mmol) was added to a mixture of5-fluoro-2-nitro-phenol (1.57 g, 10 mmol), potassium carbonate (2.76 g,20 mmol), tetrabutylammonium hydrogen sulfate (0.068 g, 0.2 mmol) andacetonitrile (30 ml), and the mixture was heated under reflux for 18 h.The cold reaction mixture was diluted with toluene and washed with 5%aqueous potassium carbonate, dried and evaporated. A part of the residue(0.631 g, 3 mmol), sodium dithionite (1.04 g, 6 mmol) in EtOH-THF-H₂O(2:1:1, 3 ml) was heated at 75° C. for 4 h. The mixture was portionedbetween dichloromethane and 15% aqueous potassium carbonate and theorganic solution dried and concentrated. The obtained residue wasdiluted with methanol (1.5 ml) and reacted with acetic anhydride (1.5ml) at 50° C. for 2 min and allowed to attend room temperature during 20min, then pyridine (4 ml) was added and the solution heated again at 50°C. for 3 min, cold and concentrated. The material was purified by silicagel chromatography (light petroleum-ethyl acetate 2:1) to give 95 mg ofthe subtitle compound.

¹H-NMR (300 MHz, CDCl₃): δ 8.28 (dd, 1H,), 7.62 (bs, 1H), 6.70-6.60 (m,2H), 5.07 (dd, 2H), 4.49 (s, 2H), 2.20 (s, 3H), 1.84 (s, 3H).

ii) N-(4-Fluoro-2-{[(2-methyl-2-oxiranyl)methyl]oxy}phenyl)acetamide

The subtitle compound was prepared fromN-[4-fluoro-2-(2-methyl-allyloxy)-phenyl]-acetamide analogously asdescribed in Example 8 ii).

¹H-NMR (300 MHz, CDCl₃): δ 8.31-8.26 (dd, 1H), 7.79 (bs, 1H), 6.75-6.65(m, 2H), 4.14 (d, 1H), 3.97 (d, 1H), 2.93 (d, 1H), 2.80 (d, 1H), 2.21(s, 3H), 1.50 (s, 3H).

APCI-MS: m/z 240 [MH⁺]

iii)N-{2-[(3-{4-[(3,4-Dichlorophenyl)oxy]-1-piperidinyl}-2-hydroxy-2-methylpropyl)oxy]-4-fluorophenyl}acetamidehydrochloride

A solution of 4-(3,4-dichloro-phenoxy)-piperidine (36 mg, 0.146 mmol),N-(4-fluoro-2-{[(2-methyl-2-oxiranyl)methyl]oxy}phenyl)acetamide (35 g,0.146 mmol) in EtOH (1 ml, 95%) was stirred for 2.5 hours at 77° C. in asealed vial. The solvent was evaporated and the residue was purified onsilica (dichloromethane-methanol, 15:1, containing 1% of NH₄OH (25%) togive 45 mg of the corresponding free amine of the title compound.

¹H-NMR of the corresponding free amine of the title compound, (400 MHz,CDCl₃): δ 8.26-8.22 (dd, 1H), 7.89 (bs, 1H), 7.31 (d, 1H), 7.01 (d, 1H),6.77-6.65 (m, 3H), 4.30 (m, 1H), 3.80 (dd, 2H), 2.93-2.81 (m, 2H), 2.67(d, 1H), 2.63-2.51 (m, 2H), 2.45 (d, 1H), 2.19 (s, 3H), 1.96 (m, 2H),1.83 (m, 2H), 1.62 (bs, 1H), 1.31 (s, 3H).

iv)N-{2-[(3-{4-[(3,4-Dichlorophenyl)oxy]-1-piperidinyl}-2-hydroxy-2-methylpropyl)oxy]-4-fluorophenyl}acetamidehydrochloride

A solution of the free amine in methanol (10 ml) was acidified with HCl(conc., 0.020 ml) to pH 3 and concentrated. The residue was coevaporatedthree times with toluene to give the title hydrochloride compound as awhite powder.

APCI-MS: m/z 485, 487 [MH⁺]

EXAMPLE 271N-(2-{(1S,2R,3S)-3-[(3S)*-3-(4-Chloro-phenoxy)-pyrroldin-1-yl]-2-hydroxy-cyclopentyloxy}-4-fluoro-phenyl)-acetamide(diastereomeric mixture)

N-{4-fluoro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide(5.0 mg, 20 μmol) and (3S,-3-(4-Chloro-phenoxy)-pyrrolidine (3.9 mg, 20μmol) were dissolved in a 2M solution of LiClO₄ in acetonitrile (0.2 ml)and heated in a sealed tube to 100° C. Dilution by ethyl acetate,neutral aqueous workup and evaporation of the solvent gave a crudeproduct which was used without further purification.

MS-APCI+: m/z 449 [M+].

EXAMPLE 272N-(5-Chloro-2-{3-[3-(3,4-difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 441.1 [MH⁺]

EXAMPLE 273N-(5-Chloro-2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-acetamide

APCI-MS: m/z 423.1 [MH⁺]

EXAMPLE 274N-(4-Cyano-2-{3-[4-(3,4-dichloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide

APCI-MS: m/z 477 [MH⁺]

EXAMPLE 275N-(4-Hydroxy-2-{(1S,2R,3S)*-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide(diastereomeric mixture)

i)N-{4-methoxy-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide(32 mg, 122 μmol) and (3S)-3-(4-Chloro-phenoxy)-pyrrolidine (24 mg, 122μmol) were dissolved in a 2M solution of LiClO₄ in acetonitrile (1 ml)and heated in a sealed tube to 100° C. Dilution by ethylacetate, neutralaqueous workup and evaporation of the solvents gave 62 mg (110%) of thecrude addition product which was reacted with bortribromide (1M inCH₂Cl₂, 0.37 mL, 371 μmol) in dichloromethane (1 mL) at room temperatureover night. The reaction was quenched with methanol (1.0 mL) and allvolatile components were evaporated. The remaining crude was subjectedto a reversed phase HPLC giving 30 mg (54%) of the title compound as adiastereomeric mixture.

MS-APCI+: m/z 447.1 [MH+].

ii) Separation of the diastereomers

The above under i) described diastereomeric mixture was subjected tochiral phase HPLC (stationary phase: Chiralpak AD; mobile phase:iso-hexane/iso-propanol/methanol/diethylamine=80:16:4:0.1) with thecompound of Example 276 as the first and the compound of Example 277 asthe second eluted stereoisomer. The assignment of the absoluteconfiguration of the respective stereoisomer beneath is set by will andexchangeable.

EXAMPLE 276N-(4-Hydroxy-2-{1S,2R,3S)-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide

¹H-NMR (400 MHz, CDCl₃; OH-protons are neglected): δ 8.02 (1H, s), 7.49(1H, d, J 8.4 Hz), 7.17 (2H, d, J 8.9 Hz), 6.71 (2H, d, J 8.8 Hz), 6.43(1H, s), 6.34 (1H, d, J 7.2 Hz), 4.76 (1H, m), 4.39 (1H, m), 4.09 (1H,m), 3.10-2.95 (3H, m), 2.89 (1H, m), 2.77 (1H, m), 2.24 (1H, m), 2.08(3H, s), 2.10-1.84 (3H, m), 1.75 (1H, m), 1.59 (1H, m).

MS-APCI+: m/z 447.1 [MH+].

[α]²²=+49.5 (CH₂C₂).

EXAMPLE 277N-(4-Hydroxy-2-{1R,2S,3R)-3-[(3S)-3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-cyclopentyloxy}-phenyl)-acetamide

¹H-NMR (400 MHz, CDCl₃; OH-protons are neglected): δ 7.75 (1H, s), 7.60(1H, d, J 8.4 Hz), 7.19 (2H, d, J 8.3 Hz), 6.73 (2H, d, J 8.6 Hz), 6.57(1H, s), 6.38 (1H, d, J 8.4 Hz), 4.77(1H, m), 4.43 (1H, m), 4.21 (1H,m), 3.09-2.94 (3H, m), 2.79 (1H, m), 2.68 (1H, m), 2.28 (1H, m), 2.08(3H, s), 2.05-1.90 (3H, m), 1.86 (1H, m), 1.53 (1H, m).

MS-APCI+: m/z 447.1 [MH+].

[α]²²=−45.2 (CH₂C₂).

The diastereomers of Examples 278 and 279 were prepared by methodsanalogous to those used to prepare the compounds of Examples 221-230 andseparated as described in Example 275 above. The absolute configurationof the respective isomers is assigned by will as mentioned above andtherefore exchangeable.

EXAMPLE 278N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide

First eluted isomer.

MS-APCI+: m/z 431.1 [MH+].

[α]²²=+72.2 (CH₂C₂).

EXAMPLE 279N-[2-({(1R,2S,3R)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide

Second eluted isomer.

MS-APCI+: m/z 431.1 [MH+].

[α]²²=−51.4 (CH₂C₂).

The diastereomers of Examples 280 and 249 were prepared by methodsanalogous to those used to prepare the compounds of Examples 221-230 andseparated as described in Example 275 above. The compound of Example 280is the first eluted isomer whilst the compound of Example 249 is thesecond eluted isomer. The absolute configuration of the respectiveisomers is assigned by will as mentioned above and thereforeexchangeable.

EXAMPLE 280N-[5-Chloro-2-({(1S,2R,3S)-3-[(3S)-3-(4-chlorophenoxy)pyrrolidinyl]-2-hydroxycyclopentyl}oxy)phenyl]acetamide

MS-APCI+: m/z 464.9 [MH+].

[α]²²=+53.0 (CH₂C₂).

EXAMPLE 281N-{5-Chloro-2-[((1S,2R,3S)*-3-{[1-(4-chlorobenzyl)-4-piperidinyl]amino}-2-hydroxycyclopentyl)oxy]phenyl}acetamide(racemicmixture)

Was prepared by analogy to Example 271 fromN-{5-chloro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]hex-2-yloxy]phenyl}acetamide(5.3 mg, 20 μmol) and 1-(4-chlorobenzyl)-4-piperidinamine (4.5 mg, 20μmol).

MS-APCI+: m/z 492 [M+].

EXAMPLE 282N-[2-({(2S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)-4-hydroxyphenyl]acetamidei) (2S)-2-[(5-Methoxy-2-nitrophenoxy)methyl]oxirane

The subtitle compound was prepared under Mitsunobu conditions fromR-(+)-glycidole (198 mg, 1 mmol), 5-methoxy-2-nitrophenol (169 mg, 1mmol), triphenylphosphine (263 mg, 1 mmol) and DEAD (157 μL, 1 mmol)using dry THF as solvent. The crude material was purified byflashchromatography on silica using mixtures of ethylacetate and heptaneas mobile phase. The appropriate fractions were pooled to give impureproduct as white crystals (175 mg). The product was contaminated withreduced DEAD in molar ratio 1:1, which is equal to a yield of thedesired product of 100 mg, 44%.

¹H-NMR (400 MHz, CDCl₃): δ 8.00 (d, 1H); 6.60 (d, 1H); 6.55 (dd, 1H);6.4 (bs, 1H, red.DEAD); 4.41 (dd, 1H); 4.22 (q, 4H, red.DEAD); 4.13 (dd,1H); 3.89 (s, 3H); 3.44-3.39 (m, 1H); 2.95 (dd, 1H); 2.92 (dd, 1H); 1.29(t, 6H, red.DEAD)

APCI-MS: m/z 226 [MH⁺]

ii)(2S)-1-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-3-(5-methoxy-2-nitrophenoxy)-2-propanol

The subtitle compound was prepared by analogy to Example 1 (ii) from (i)(169 mg, 0.43 mg) and (3S)-3-(4-chlorophenoxy)pyrrolidine (85 mg, 0.43mmol). The product was obtained as a yellow oil and was used withoutfurther purification.

APCI-MS: m/z 423, 425 [MH⁺]

iii)(2S)-1-(2-Amino-5-methoxyphenoxy)-3-[(3S)-3-(4-chlorophenoxy)pyrrolidinyl]-2-propanol

The subtitle compound was prepared in analogy of Example 253 iii) from(ii) (0.43 mmol). The product obtained (colourless oil, 163 mg) was amixture of the desired product and reduced DEAD in molar ratio 5:1. Thesubstance was used as it was.

¹H-NMR (400 MHz, CDCl₃): δ 7.23 (d, 2H); 6.77 (d, 2H); 6.67 (d, 1H);6.49 (d, 1H); 6.41 (bs, red.DEAD); 6.39 (dd, 1H); 4.83-4.77 (m, 1H);4.22 (q, red.DEAD); 4.14-4.07 (m, 1H); 4.01 (d, 2H); 3.75 (s, 3H);3.01-2.91 (m, 2H); 2.88-2.72 (m, 3H); 2.62 (dd, 1H); 2.29 (hex, 1H);2.06-1.96 (m, 1H); 1.29 (t, red.DEAD)

APCI-MS: m/z 393, 395 [MH⁺]

iv)N-[2-({(2S)-3-[(3S)-3-(4-Chlorophenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)-4-methoxyphenyl]acetamide

To a solution of compound iii) (157 mg) in a mixture of acetonitrile (10mL) and water (2 mL) acetic anhydride (1 mL) was added and the mixturewas stirred at ambient temperature overnight. 1.5M sodiummethoxid inmethanol (1 mL) was added and the stirring continued for 1 h. Afterevaporation the residue was taken up in ether and water. The subtitleproduct was obtained from the organic phase as a colourless oil (155mg).

¹H-NMR (400 MHz, CDCl₃): δ 8.18 (d, 1H); 7.95 (bs, 1H); 7.24 (d, 2H);6.78 (d, 2H); 6.56-6.52 (m, 2H); 4.85-4.78 (m, 1H); 4.22 (q, red.DEAD);4.10-4.02 (m, 2H); 4.00-3.92 (m, 1H); 3.78 (s, 3H); 3.00-2.91 (m, 2H);2.87-2.73 (m, 3H); 2.53 (dd, 1H); 2.36-2.25 (m, 1H); 2.17 (s, 3H);2.07-1.99 (m, 1H); 1.29 (t, red.DEAD)

APCI-MS: m/z 435, 437 [MH⁺]

v)N-[2-({(2S)-3-[(3S)-3-(4-Chlorophenoxy)pyrroldinyl]-2-hydroxypropyl}oxy)-4-hydroxyphenyl]acetamide

The title compound was prepared by analogy to Example 254 from iv) (150mg). The product obtained after lyophilization was a white amorphoussolid (101 mg, 57%).

¹H-NMR (400 MHz, CDCl₃+1 drop DMSO-d₆): δ 8.7 (bs, 1H); 8.34 (s, 1H);8.73 (d, 1H); 7.18 (d, 2H); 6.73 (d, 2H); 6.40-6.31 (m, 2H); 4.99-4.93(m, 1H); 4.4-1.9 (bm, 6H); 4.31-4.23 (m, 1H); 3.88-3.78 (m, 2H);3.39-3.25 (m, 2H); 2.4-2.2 (m, 2H); 2.07 (s, 3H)

APCI-MS: m/z 421, 423 [MH⁺]

THP-1 Chemotaxis Assay

Introduction

The assay measured the chemotactic response elicited by MIP-1α chemokinein the human monocytic cell line THP-1. The compounds of the Exampleswere evaluated by their ability to depress the chemotactic response to astandard concentration of MIP-1α chemokine.

Methods

Culture of THP-1 Cells

Cells were thawed rapidly at 37° C. from frozen aliquots and resuspendedin a 25 cm flask containing 5 ml of RPMI-1640 medium supplemented withGlutamax and 10% heat inactivated fetal calf serum without antibiotics(RPMI+10% HIFCS). At day 3 the medium is discarded and replaced withfresh medium.

THP-1 cells are routinely cultured in RPMI-1640 medium supplemented with10% heat inactivated fetal calf serum and glutamax but withoutantibiotics. Optimal growth of the cells requires that they are passagedevery 3 days and that the minimum subculture density is 4×10+5 cells/ml.

Chemotaxis Assay

Cells were removed from the flask and washed by centrifugation inRPMI+10% HIFCS+glutamax. The cells were then resuspended at 2×10+7cells/ml in fresh medium (RPMI+10% HIFCS+glutamax) to which was addedcalcein-AM (5 μl of stock solution to 1 ml to give a final concentrationof 5×10⁻⁶M). After gentle mixing the cells were incubated at 37° C. in aCO₂ incubator for 30 minutes. The cells were then diluted to 50 ml withmedium and washed twice by centrifugation at 400×g. Labelled cells werethen resuspended at a cell concentration of 1×10+7 cells/ml andincubated with an equal volume of MIP-1α antagonist (10⁻¹⁰M to 10⁻⁶Mfinal concentration) for 30 minutes at 37° C. in a humidified CO₂incubator.

Chemotaxis was performed using Neuroprobe 96-well chemotaxis platesemploying 8 μm filters (cat no. 101-8). Thirty microliters ofchemoattractant supplemented with various concentrations of antagonistsor vehicle were added to the lower wells of the plate in triplicate. Thefilter was then carefully positioned on top and then 25 μl of cellspreincubated with the corresponding concentration of antagonist orvehicle were added to the surface of the filter. The plate was thenincubated for 2 hours at 37° C. in a humidified CO₂ incubator. The cellsremaining on the surface were then removed by adsorption and the wholeplate was centrifuged at 2000 rpm for 10 minutes. The filter was thenremoved and the cells that had migrated to the lower wells werequantified by the fluorescence of cell associated calcein-AM. Cellmigration was then expressed in fluorescence units after subtraction ofthe reagent blank and values were standardized to % migration bycomparing the fluorescence values with that of a known number oflabelled cells. The effect of antagonists was calculated as % inhibitionwhen the number of migrated cells were compared with vehicle.

1. A compound of general formula

m is 0, 1, 2 or 3; each R¹ independently represents halogen, cyano,nitro, carboxyl, hydroxyl, C₃-C₆ cycloalkyl, C₁-C₆ alkoxy, C₁-C₆alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —NR⁹R¹⁰, C₃-C₆cycloalkylamino, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl, C₁-C₆alkylcarbonylamino, sulphonamido, C₁-C₆ alkylsulphonyl, —C(O)NR¹¹R¹²,—NR¹³C(O)—(NH)_(p)R¹⁴, phenyl, or C₁-C₆ alkyl optionally substituted bycarboxyl or C₁-C₆ alkoxycarbonyl; p is 0 or 1; X represents an oxygen orsulphur atom or a CH₂, CH(CH₃), OCH₂, CH₂O, CH₂NH, NH or carbonyl groupand Y represents a CH group; Z¹ represents a bond or a group (CH₂)_(q)where q is 1 or 2; Z² represents a bond or a group CH₂, with the provisothat Z¹ and Z² do not both simultaneously represent a bond; Q representsan oxygen or sulphur atom or a group CH₂ or NH; R² represents a group

n is 0, 1 or 2; each R³ independently represents a C₁-C₆ alkyl, C₁-C₆alkoxycarbonyl, —CH₂OH or carboxyl group; R⁴, R⁵, R⁶ and R⁷ eachindependently represent a hydrogen atom or a C₁-C₆ alkyl group, or R⁴,R⁵, R⁶ and R⁷ together represent a C₁-C₄ alkylene chain linking the twocarbon atoms to which they are attached to form a 4- to 7-memberedsaturated carbocycle, or R⁵, R⁶ and R⁷ each represent a hydrogen atomand R⁴ and R⁸ together with the carbon atoms to which they are attachedform a 5- to 6-membered saturated carbocycle; R⁸ represents a hydrogenatom, a C₁-C₆ alkyl group or is linked to R⁴ as defined above; R⁹ andR¹⁰ each independently represent a hydrogen atom or a C₁-C₆ alkyl group,or R⁹ and R¹⁰ together with the nitrogen atom to which they are attachedform a 4- to 7-membered saturated heterocycle; R¹¹ and R¹² eachindependently represent a hydrogen atom or a C₁-C₆ alkyl groupoptionally substituted by C₁-C₆ alkoxycarbonyl; R¹³ represents ahydrogen atom or a C₁-C₆ alkyl group; and R¹⁴ represents a hydrogenatom, or a C₁-C₆ alkyl group optionally substituted by carboxyl, C₁-C₆alkoxy or C₁-C₆ alkoxycarbonyl; provided that when X is an oxygen atomor a group CH₂, Y is CH, Z¹ and Z² each represent a group CH₂ and Q isan oxygen atom, then R² is other than an unsubstituted indolyl group; ora pharmaceutically acceptable salt or solvate thereof.
 2. A compoundaccording to claim 1, wherein X represents an oxygen atom or a CH₂,OCH₂, CH₂O, NH or carbonyl group.
 3. A compound according to claim 1,wherein Q represents an oxygen atom.
 4. A compound according to claim 1,wherein R² represents a group


5. A compound of formula (I″), or a pharmaceutically acceptable salt orsolvate thereof, as defined in claim 1 being selected from:1-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol,1-(7-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,1-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol,1-(7-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,1-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol,1-(7-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,1-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)-propan-2-ol,1-(7-{3-[3-(3,4-Difluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,1-(7-{3-[4-(3,4-Dichloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,1-(7-{3-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-2-hydroxy-propoxy}-indol-1-yl)-ethanone,N-(3-{3-[3-(3,4-Dichloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-naphthalen-2-yl)-acetamide,andN-(3-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-naphthalen-2-yl)-acetamide.6. A process for the preparation of a compound of formula (I″) asdefined in claim 1 which comprises, (a) reacting a compound of generalformulaR—H  (II″) wherein R is as defined in formula (I″), with a compound ofgeneral formula

wherein Q, R², R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in formula (I″); or(b) reacting a compound of general formula

wherein R, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in formula (I″), with acompound of general formulaL¹-Q-R²  (V″) wherein L¹ represents a hydrogen atom or an activatinggroup and Q and R² are as defined in formula (I″); and optionallythereafter converting the compound of formula (I″) to a further compoundof formula (I″); and, if desired, forming a pharmaceutically acceptablesalt or solvate of the compound of formula (I″).
 7. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I″), or a pharmaceutically acceptable salt or solvatethereof, as claimed in claim 1 in association with a pharmaceuticallyacceptable adjuvant, diluent or carrier.
 8. A process for thepreparation of a pharmaceutical composition, the process comprisingmixing a therapeutically effective amount of a compound of formula (I″),or a pharmaceutically acceptable salt or solvate thereof, as claimed inclaim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier.9. A method of treating rheumatoid arthritis in a patient suffering fromarthritis, which method comprises administering to the patient atherapeutically effective amount of a compound of formula (I″), or apharmaceutically acceptable salt or solvate thereof, as claimed inclaim
 1. 10. A method of treating asthma in a patient suffering fromasthma, which method comprises administering to the patient atherapeutically effective amount of a compound of formula (I″), or apharmaceutically acceptable salt or solvate thereof, as claimed inclaim
 1. 11. A method of treating multiple sclerosis in a patientsuffering from multiple sclerosis, which method comprises administeringto the patient a therapeutically effective amount of a compound offormula (I″), or a phamiaceutically acceptable salt or solvate thereof,as claimed in claim 1.